Hypertensive Disorders in Pregancy - 7

In our last post on the subject of hypertensive disorders in pregnancy, we pointed out that once preeclampsia has developed, we are limited in our ability to “treat” the condition. Indeed, the only situations I have seen in which the clinical syndrome of preeclampsia has resolved have been those in which an adverse fetal condition was first reversed. An example of this is severe fetal anemia (usually associated with fetal hydrops) secondary to isoimmunization or Parvovirus infection that responded to intrauterine transfusion. Nevertheless, there are other circumstances in which we may be able to prevent or reduce the risk for preeclampsia.

As mentioned in our third post on this subject, there are several well-known prepregnancy and intrapregnancy risk factors for preeclampsia. While we cannot change a woman’s race or age, or the presence of a first pregnancy, new partner, or multiple gestation, there are two groups of women we can identify from this list who would probably benefit from more aggressive medical management to reduce their risks for preeclampsia. There are those who previously had a pregnancy complicated by preeclampsia and those who have not (or who have never been pregnant) and/or have significant risk factors or medical conditions that might lend themselves to medical intervention as a preventive measure prior to conception or very early in pregnancy.

In the first case (previous history), we know that recurrence risks for preeclampsia are correlated with the severity of disease and the earlier in gestation the preeclampsia occurred. Indeed, rates of recurrence for a history of severe, early onset preeclampsia approach 40-50% in some studies. So we do have a ready-made subgroup of women to which we should direct efforts at prevention. Similarly, women who have hypertension, renal disease, diabetes, polycystic ovary syndrome and other conditions associated with insulin resistance, an autoimmune disease, or known autoimmune or genetic thrombophilia also shake out as a group to which extra attention should be directed.

So, what can we do to help these women? The first thing we would recommend is to optimize their medical conditions and general health. If a woman is overweight, then a weight reduction and exercise program should be encouraged prior to conception with some realistic ‘goals’ in mind before attempting pregnancy. If she is hypertensive, diabetic, or has another treatable medical condition, control of this (these) should be optimized, again, prior to conception. In women who have polycystic ovary syndrome or other conditions associated with insulin resistance, the use of an ‘insulin-sensitizing’ drug such as metformin may play a role, can be started before conception, and can be continued during the pregnancy.

Beyond this, almost all efforts at intervention would have to be considered ‘empiric’. In my own practice, I offer all of these women with significant risk factors the regimen of low-dose aspirin (81 mg daily) and supplemental folic acid (usually 2-4 mg daily). If a woman has a known autoimmune or genetic thrombophilia, I have a low threshold for adding prophylactic use of heparin or low molecular weight heparin; and, if there is a history (or strong family history) of venous or arterial thrombosis, therapeutic doses of these same drugs. The latter are relatively safe to use in pregnancy (they do not cross the placenta), their doses can be monitored and adjusted as the pregnancy progresses, and at least one study would support their use in the ‘prevention’ of preeclampsia (Sergio, et al., Hypertens Pregnancy 2006;25:115).

I have on occasion also used both prophylactic and therapeutic doses of heparin and low molecular weight heparin in women who have had severe early onset preeclampsia in a previous pregnancy (or more than one) and no identifiable thrombophilia or other risk factor for which these drugs would ordinarily be indicated. Under these circumstances, once the pregnancy is well-established, and if normal fetal growth and Doppler flow studies can be documented (usually by 28 weeks gestation), I will discontinue these drugs.

I will close this series on hypertensive disorders in pregnancy with (perhaps) one last post wherein I will address other possible diagnostic, therapeutic, and possibly preventive approaches that might be taken in the future to reduce the frequency and severity of preeclampsia…

Labels: Preeclampsia treatment and prevention

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Hypertensive Disorders of Pregnancy - 6

Well, I was away again this weekend. Drove to Indianapolis for my niece’s wedding. That area, like so much of the rest of the country, has been suffering from a drought, but it decided to come to an end this weekend. Of course, the wedding rehearsal dinner, wedding itself, and the reception were all planned for the outdoors, and went forward despite the downpour. The weather, as usual, showed no respect for protocol. But, everyone had a great time. Our congratulations, love, and best wishes (for everything but twins) to the beautiful couple, Karen Wilson and Daniel Wielunski.

Anyway, let’s chat a little more about preeclampsia. The next question to address is how do we treat preeclampsia? Believe it or not, the answer to that is rather simple. In most cases, we don’t. Since the most common forms of preeclampsia are the ‘end-stage’ manifestation of events occurring earlier in pregnancy, we cannot correct the conditions (and probably never will be able to) once we have gotten to the point of preeclampsia. About all we can do is stabilize the mother and the baby temporarily (in the U.S., this involves primarily the use of bed rest, magnesium sulfate, antihypertensives, and fetal assessment) and then deliver, regardless of the gestational age, whenever the maternal and/or the fetal condition deteriorate to the point that it is dangerous for either/both to continue the pregnancy. In some cases, we buy a fair amount of time, and in others delivery is required almost immediately. The old adage that the sun should not set on a severely preeclamptic woman until the placenta is in the bucket to be sent to pathology holds a lot of truth. Even then, the most severely affected women (and sometimes those not so severely affected before delivery) may continue to deteriorate for days after the source of the problem (the placenta) is removed because of the hypertension, endothelial cell damage, consumptive coagulopathy, kidney and liver damage, brain swelling, and fluid shifts that occur before and may continue after delivery! Since at least two-thirds of preeclampsia occurs in women having their first babies, and we currently have no reliable and cost-effective means of identifying those at greatest risk, this is about the only recourse we have to ‘manage’ the bulk of cases of preeclampsia.

Some efforts have been made at what would have to be considered ‘empiric preventive therapy’ in an effort to reduce the number of patients who develop preeclampsia and its complications. In the general obstetrical population, the only ‘therapy’ to date that has shown any real promise is low-dose aspirin (81 mg), preferably begun very early (if not before in my opinion) in pregnancy. Recent metanalyses by Askie, et al., (Lancet 2007;369:1791-98) and Duley, at al., ((Cochrane Database Rev 2007;April 18(2)) suggested small, but significant, benefits of aspirin therapy in randomized trials involving 32,217 and 37,560 women, respectively. Askie reported a 10% reduction in risk of developing preeclampsia, delivering before 34 weeks, and serious adverse pregnancy outcome. Importantly, they also demonstrated “no identifiable risks of therapy.” Duley reported comparable results: 17% reduction in preeclampsia; 8% reduction in risk of preterm birth; 10% reduction in ‘small-for-gestational-age (SGA)’ babies; 14% reduction in fetal/neonatal deaths. The numbers might not seem great, but this is one of those situations where any little bit helps and represents a significant improvement in outcomes, a minimal investment in cost of medical therapy, and a significant cost savings to the health care system. Indeed, if this data holds, and I believe it will, we should soon be making a strong case for including aspirin in the category of ‘prenatal vitamins and folic acid.’

Other attempts at prevention of preeclampsia have had sensible reasons for being tried but have been very disappointing. High-dose vitamins C and E (‘antioxidants’) showed no benefit and may actually be accompanied by increased risk for complications (Rumbold, et al., NEJM 2006;354:1796-1806). Cochrane Database System Reviews have also shown no benefit of diuretics (Churchill, et al., 2007;Jan 24(1):CD004451); progesterone (Meher, et al., 2006;Oct 18(4):CD006175); garlic (Meher, et al., 2006;Jul 19:CD006065); or fish oil and other prostaglandin precursors (Makrides, et al., 2006;Jul 19:CD003042). The benefits of calcium supplementation have shown mixed results. Although an FDA review showed no benefit (Trumbo, et al., Nutr Rev 2007;65:78-87), another Cochrane Database Review suggested that there might be some (Hofmeyr, et al., 2006;Jul 19(3):CD001059).

In the next post, we will look at a group of patients who are at significant risk for developing preeclampsia, those who had it previously and others who have medical conditions that put them at risk, and review the current thinking on what we can do to help them….

Labels: Preeclampsia treatment and prevention

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Hypertensive Disorders in Pregnancy - 5

In our last post on this subject, we described an abnormality of placental development, incomplete or abnormal invasion of the maternal spiral arterioles by fetal placental cells (trophoblasts) early in pregnancy, as perhaps the most common sentinel event associated with preeclampsia later in pregnancy. This abnormality of placentation can, albeit variably, restrict blood flow into the placental bed from the spiral arterioles on the maternal side and can also limit the size, arborization (branching), and the total surface area of the fetal-placental villi that are bathed by the maternal blood that enters the placental bed. This is significant because all the oxygen and nutrients the baby gets to survive have to cross the surface of the villi to get into the fetal circulation. If the abnormality of placentation is extensive enough, this will eventually limit the growth of the baby and stress the capacity of the placenta to maintain a ‘healthy’ environment for both baby and placenta. At the risk of taking an overly simplistic approach, it seems almost intuitive that preeclampsia results then from an attempt on the part of the placenta to improve its condition by whatever ‘homeostatic’ mechanisms it has at its disposal. The ultimate goal of these homeostatic mechanisms seems to be an attempt to increase the amount of maternal blood (oxygen?) actually flowing into the placental bed.

Over the years, many clinical observations have been made that are consistent with this model of abnormal placentation and also with the attempt of the placenta to improve its lot in life. Let me give you a few examples to illustrate these points. In circumstances of normal placentation, that is a pregnancy not destined to end in preeclampsia, the mother’s blood pressure usually starts to drop at the transition of first to second trimester. This timing of the blood pressure drop coincides with the time when the adequately ‘invaded and plugged’ spiral arterioles become unplugged and the now sac-like ‘remodeled’ vessels allow the maternal blood to flow freely into the placental bed with very little resistance. The placental bed thus becomes an ‘arteriovenous shunt’ and as a consequence the maternal blood pressure falls.

With abnormal invasion of the spiral arterioles, the vessels remain narrow, coiled and responsive to factors that can cause them to constrict. As a result, the ‘midtrimester drop’ in maternal blood pressure either does not occur or is much less dramatic than in normal circumstances. This abnormality of placentation in women at increased risk to become preeclamptic was suggested by observations made half a century ago. When pressors (drugs that cause blood vessels to constrict and raise blood pressure) such as norepinephrine are infused into ‘normal’ pregnant women, they have a very blunted response to the blood pressure elevating effects of these drugs. However, when these drugs are given to women who eventually became preeclamptic, their blood pressure rises the same as it would if they were not pregnant at all. Can’t you see those tight little spiral arterioles clamping down right now?!? Decreasing blood flow to the placenta just cannot be a good thing.

In the last 25 years, we have figured out a less invasive way of ascertaining abnormalities of both spiral arteriole remodeling and fetal placental vascular development. Using Doppler flow velocimetry, we can assess resistance to blood flow in vessels by simply using ultrasound. Since the blood vessel abnormalities occur early in pregnancy, Doppler flow studies can show abnormal resistance patterns often long before the onset of preeclampsia and be used to identify ‘women at risk.’ Indeed, increased resistance in the uterine arteries (reflecting increased resistance ion the spiral aretrioles) beginning early in the second trimester, and in the fetal umbilical arteries (reflecting increased resistance in the placental villi), sometimes as early as 16-20 weeks, are well-correlated with later development of fetal growth restriction, preeclampsia, fetal deaths, need for early delivery, and risk for cesarean delivery because of babies developing nonreassuring fetal heart rate patterns secondary to oxygen deprivation.

So, if the placentation is abnormal, how is it that the placenta eventually recognizes and responds to its hostile environment to try to improve its (and the baby’s) situation. We don’t know for sure, but I believe the clinical features of preeclampsia reflect the placenta’s efforts. As we mentioned in our first posts on this subject, preeclampsia is characterized by intense vasospasm (constriction) of the mother’s blood vessels. Vasospasm causes the mother’s blood pressure to rise and suggests that the placenta is using the only means it has at its disposal (whatever the mechanism) to force more blood into the placental bed from the maternal side, somehow forcing the mother’s blood pressure higher. Unfortunately, the narrow abnormal maternal spiral arterioles only have so much capacity to allow blood to pass through them; and, it is possible that the placenta’s production of factors that lead to vasoconstriction of peripheral blood vessels might also cause some constriction of the spiral arterioles as well, thereby worsening an already deteriorating situation. Such a ‘vicious cycle’, once started, could rapidly lead to the full-blown picture of preeclampsia: vasospasm, hypertension, plasma volume constriction, endothelial cell damage, and activation of the coagulation pathways.

In our next post, we will present an overview of the limited information we have available to us regarding interventions we might take to reduce the risk of preeclampsia…

Labels: Doppler flow velocimetry, preeclampsia

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Comments on Your Comments!

I have been ill myself (nothing serious, just miserable) for the past week and have had a hard time writing much except to respond to some of your questions. When I can get my brain to work again, I promise to finish up my series on “Hypertensive Disorders of Pregnancy” in the near future, but before we do, let me digress for one day…

Yesterday, I received a very nice comment from JRae who had read my series on “Recurrent Early Pregnancy Loss.” She said, “Thank you so very much for taking the time to put this series of blogs together. I especially appreciate that even after concluding the series you are still responding to those leaving questions on the posts…. I think many…would benefit from your blog as I have (if they haven't already found you!). Thanks again. –Jrae.” Her commment reminded me that for awhile now I have wanted to pass along some comments regarding comments to my readers.

In my very first post, almost a year ago, I said “…my goals for this site are fairly straightforward. I would like to provide you with accurate information related to normal and complicated pregnancies. As I tell all my patients, NO question is insignificant, although you may be surprised that the answer is often much more complicated than the question itself. Where the facts are known, and well-established, mainstream information will be provided. When the issues are more controversial, or do not have widely agreed upon answers, I will make an honest attempt to provide unbiased information, presenting the various opinions on “both sides of the fence,” reserving the right in the end to tell you where I stand on the issue and why. I look forward to beginning a dialog with you on this blog. And, above all I would like us to have some fun as we exchange experiences and communications over time.”

Unfortunately, this site is not set up in a way that we can easily have a running dialog with readers. Quite frankly, since I have a ‘day (and frequently, night) job’, that would be difficult anyway since I write these posts in my free time. I have tried to respond to as many comments and questions as possible, but since my ‘comments’ only appear in the comments section of the blog in which the original comment was made, I never know if the original ‘commenters’ ever find their way back there to read my responses. It is also a shame that many of my responses would probably make, or provide the basis, for a ‘blog’ in and of themselves and I am sure there are many other readers that might benefit from the questions who never have the opportunity to see my answers.

Anyway, I would like to continue to respond to your questions, but have several comments of my own! First, I have found that many of your questions are already answered in the posts or in the comments of other readers, so please check out the original post and related ones as well. If you do need clarification or have a question about a post, or about your own situation, please provide me with thorough and accurate information and as specific a question as possible. Remember, I can only work with what you give me and have no delusions of grandeur with regard to being able to read minds or between the lines!

When I do respond, please be aware of the limitations of my answers. I can provide some thoughts, some information, some clarification of something you do not understand, some questions you might ask your providers, and maybe even a correct solution (given enough information) to your particular problem, but I cannot possibly understand your entire situation and I certainly CANNOT replace your own doctors in providing all the answers for your care. As wonderful as the internet is, it does not take the place of the face-to-face and hands-on attention of a physician who knows you well. So, don’t be afraid to ask them your questions, the same ones you are asking me! If they tell you something and you do not understand, then ask them to explain it a way that you do. Don’t ever leave your doctor’s office with big questions lingering in your heads, unless of course your doctor tells you up front that “I don’t know myself at this time.”

Anyway, thanks to all of you for reading and for the feedback and questions you have raised in response to the posts. I hope you have gotten as much out of this blog as I have!

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Hypertensive Disorders in Pregnancy - 4

In our last post, we mentioned that preeclampsia is often the end-stage clinical manifestation of irreversible pathologic changes that take place early in pregnancy. Indeed, there is good evidence that abnormal early placental development plays a key role in setting the stage for a woman to eventually develop preeclampsia, especially in its most severe forms. We know that pregnancy is a prerequisite for preeclampsia, but the presence of a baby is not! Some of the most severe and earliest onset cases (sometimes before 20 weeks) of preeclampsia occur with ‘molar pregnancies’ characterized by abnormal placental tissue and no baby. However, molar pregnancies do not typify the more common placental abnormalities seen in preeclampsia. The example does make the point, however, that all you need is a placenta that isn’t ‘happy’ with its intrauterine environment and somehow this can lead to the clinical picture of preeclampsia. So, what are the placental abnormalities that culminate in preeclampsia.

Once upon a time, in a post long, long ago, we talked about early embryonic development. Shortly after the early embryo (the zygote) first enters the uterus, it begins to ‘differentiate’ into some cells that will eventually form the baby and others that will eventually form the placenta. At this point, the ‘baby’ is called a ‘blastocyst’ and it must attach to a favorable location on the inner lining of the uterus (the endometrium) within about 48 hours. Over the next week (and prior to the time of the next expected menstrual period), the blastocyst solidifies its attachments to the endometrium and, while continuing to differentiate into tissues that will eventually form the placenta or the baby, literally buries itself in the endometrial lining.

The early placental cells (trophoblasts) first anchor the blastocyst to the endometrium. Over the next 6 weeks (the embryonic period), as all the major internal and external structures of the baby are developing, some of the trophoblasts undertake an essential and, potentially, dangerous journey through the maternal endometrial tissues where they are exposed to both nonspecific and specific mediators of the mother’s immune response. Under optimal (normal) circumstances (if the mother’s immune responses help them out), at the end of this journey the trophoblasts will actually invade and replace (remodel) the lining and muscular walls of the mother’s ‘spiral arterioles’ in the endometrium (between 6-10 weeks) and upper third of the myometrium (between 14-22 weeks).

Ultimately, this ‘decidualization’ of the spiral arterioles transforms them from narrow, coiled, high resistance blood vessels into structures (‘uteroplacental vessels’) with low resistance and high capacitance, through which blood readily flows to fill the placental bed. During this process, these vessels also lose their ability to constrict in response to common factors/conditions that cause other blood vessels in the mother’s body to constrict, thereby assuring blood flow to the placenta, even under circumstances such as stress that might otherwise interrupt placental perfusion and cause damage to the baby.

We have known for several decades that abnormal invasion of the spiral arterioles is characteristic of preeclampsia, however, it has only been in recent years that another very important part of this process has been recognized. It appears that with normal placental development, in the first wave of invasion, the fetal trophoblasts not only replace the lining and muscular wall of the endometrial portion of the spiral arterioles, but also PLUG these vessels at their tops, thereby limiting blood flow into the growing placental bed during first trimester. This seems somewhat counter-intuitive. Don’t the developing baby and placenta need all the oxygen they can get from the maternal blood? Apparently not! Indeed, it appears that until a certain stage of development (10-12 weeks), oxygen might actually be toxic to the fetal tissues.

Furthermore, limiting the amount of oxygen also seems to promote the elaboration of certain growth and angiogenic (blood vessel growth promoting) factors that allow the placenta to grow (arborization of the placental villi that are bathed by maternal blood in the placental bed) to a size that will be necessary to transport sufficient oxygen and nutrients to the baby at later stages of the pregnancy. Anyway, even though we do not understand how, it appears that in pregnancies destined to develop preeclampsia, the normal ‘plugging’ of the spiral arterioles does not occur and this results not only in a smaller placenta, but a situation in which blood flow is impeded from both the maternal side (spiral arterioles) into the placental bed and the fetal side, through the vessels of the truncated placental villi.

Although these abnormalities in placental development do not result in preeclampsia until later in pregnancy, there are certain things we can look for during pregnancy that can suggest these abnormalities are present and the pregnancy is ‘at risk’. In the next post we will discuss them and some of the clinical features of preeclampsia that develop, probably, as the placental response to the ‘hostile’ environment that eventually results from these changes…

Labels: placental abnormalities; spiral arterioles, preeclampsia

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Hypertensive Disorders in Pregnancy - 3

In our last two posts, we have discussed the general significance of hypertensive disorders in pregnancy and the spectrum of pregnancy-induced hypertensive disorders classified as preeclampsia. The problem with preeclampsia is that most of the time it is the end-stage manifestation of irreversible pathologic changes that took place early in pregnancy and by the time we recognize that a pregnant woman is developing the condition, there is little if anything we can do to ‘treat’ it. I will elaborate on these points in a subsequent post, but the bottom line is that we will have to learn to identify women ‘at risk’ by the end of first trimester and early second trimester if there is to be any hope of decreasing the incidence and severity of preeclampsia. Theoretically and, perhaps, practically in the not-to-distant future, we should be able to do just that.

For the time being, however, we must rely on known risk factors to identify a subset of women in whom it is appropriate to offer some form of medical intervention. With this in mind, the questions arise: What are risk factors for preeclampsia?; Which are those that may be most amenable to intervention?; What sort of interventions are possible and practical?; and, When should such interventions be started? The common risk factors, occurring before and during pregnancy are well-known and there is little argument about their association with preeclampsia:

· First pregnancies and, to a lesser degree, first pregnancies with a new partner
· Multiple gestations
· Chronic hypertension
· Chronic kidney disease
· African-American ethnicity
· Women over age 35
· History of pregnancy-induced hypertension
· Obesity
· Pregestational diabetes – especially long-standing with kidney or vascular disease
· Gestational diabetes
· Autoimmune diseases such as systemic lupus erythematosus
· Family history of preeclampsia
· Abnormal maternal serum pregnancy markers (AFP, hCG, estriol, inhibin A)
· Isoimmunization with fetal hydrops (and other conditions with hydrops)
· Molar and partial molar pregnancies

Other, less well-known, risk factors also seem to place a woman at greater risk for hypertensive disorders in pregnancy as well and among the more likely to do so are:

· Polycystic ovary syndrome
· Insulin resistance and ‘metabolic syndrome’
· Hyperthyroidism
· Antiphospholipid antibody syndrome
· Thrombophilias (genetic abnormalities of the coagulation system)
· Hyperhomocysteinemia
· Pregnancies achieved by egg donation

Sticking to the mantra that “the best prenatal care begins prior to conception,” the best opportunity for risk assessment and potential intervention starts with a preconceptional or interconceptional (between pregnancy) visit. Some of the interventions are obvious. If a patient has an underlying medical condition such as diabetes, chronic hypertension, thyroid disease, systemic lupus, etc., those medical conditions should be ‘optimized’ with treatment that is ‘safe’ for pregnancy before ever conceiving. Women who are overweight, and have any accompanying condition (e.g. PCOS, hypertension, diabetes, insulin resistance) should attempt a supervised exercise and diet weight reduction program prior to conception (personally, I believe ‘Atkins’ and exercise’ is ideal for these women!).

Preeclampsia is often considered to be a ‘disease of women carrying their first babies’ and indeed it occurs at least twice as often under these circumstances as in women who have previously had a baby. Since we have no early diagnostic or reliable screening test to tell us which of these first-time pregnant women are at risk, the most we can hope to do at present is address beforehand any medical issues, optimize control of such conditions, give them prenatal vitamins with folic acid, and follow them carefully during their pregnancies. If a major risk factor taken from the list above is identified, other options for intervention should be considered, but that discussion is beyond the scope of today’s post.

I have learned through the years that two of the most significant predictors of preeclampsia are previous history of preeclampsia and family history of the same. A rule of thumb is that the more severe the preeclampsia, the earlier it occurred in a previous pregnancy, the more complications with which it was associated (e.g. eclampsia, HELLP syndrome, severe fetal growth restriction, placental abruption, decreased amniotic fluid, fetal or neonatal death, placental vascular abnormalities) the greater the likelihood for recurrence with a subsequent pregnancy, even if no other ‘risk factor’ is ever identified. The fact that we haven’t ‘identified’ such risk factors probably speaks more to our current level of ignorance regarding these matters than to their nonexistence!

By the way, if you hadn’t noticed, there is one ‘risk factor’ that is conspicuously absent from the lists above – SMOKING! I am almost afraid to mention this because there is nothing that justifies the habit in pregnancy, but fact of the matter is that smoking appears to REDUCE the risk of preeclampsia. As has been recently summarized by England, et al., (Front Biosci 2007;12:2471-83), the “beneficial effects” of smoking are present in a “dose-related” fashion and are consistently found regardless of parity, number of babies, and severity of preeclampsia that is found. The overall risk reduction approaches 50%! Believe me, this is not an endorsement of smoking during pregnancy (or ever for that matter), but perhaps someday we will be able to identify a relatively ‘safe’ by-product of tobacco that can help prevent or reduce the severity of preeclampsia!

In our next post, we will look at the role of abnormal early placental development in setting the stage for developing preeclampsia and some of the ongoing evaluation that can be done during pregnancy to anticpate risk…

Labels: Hypertension in pregnancy, preeclampsia risk factors

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Hypertensive Disorders in Pregnancy - 2

The term preeclampsia applies to a spectrum of disorders that are pregnancy-dependent, all accompanied (usually) by some degree of hypertension at some point in their evolution. Preeclampsia is subdivided into categories based on the severity of hypertension and accompanying signs, symptoms, and laboratory abnormalities. Although the actual cause of preeclampsia is not known, it is probably the consequence of a placental compensatory mechanism (rather than dysfunction) in response to a suboptimal or even hostile local environment that is the end result of abnormalities of early placental development and growth and/or from conditions that impair placental function later in pregnancy. We will discuss some of the pathologic correlates, clinical characteristics, and risk factors for preeclampsia in a subsequent post, but today let’s focus on defining the various categories of preeclampsia.

Mild preeclampsia is defined as hypertension developing during pregnancy, accompanied by the onset of proteinuria (protein in the urine). Proteinuria is defined as greater than or equal 300 mg/L in a 24 hour urine specimen (or greater than or equal 1+ urine protein by ‘dipstick’ on two random specimens taken 6 or more hours apart). The presence of generalized edema (soft tissue fluid accumulation), or 5 lb or more weight gain (usually mostly fluid retention) within a week, often accompany the hypertension and proteinuria, and may alert us to the onset of the condition, but is not required for the strict diagnosis of preeclampsia. If the criteria for hypertension and proteinuria are met, a pregnant woman remains a ‘mild preeclamptic’ unless she develops evidence of one of the more severe manifestations of preeclampsia.

The diagnosis of severe preeclampsia requires the presence of only one of the following:
· BP greater than or equal to 160 mmHg systolic or 110 mmHg diastolic on two occasions 6 or more hours apart at bedrest
· Proteinuria greater than or equal to 5 g in 24 hr (or 3-4+ on two dipstick specimens 4 or more hours apart)
· Oliguria = urine output less than 500 mL in 24 hr
· Abnormal liver function tests
· Thrombocytopenia (platelet count less than 100,000/mm3)

Conditions that also help to define severe preeclampsia when present include:
· Cerebral or visual disturbances – headache, blurred vision, scotomata, blindness, altered consciousness
· Pulmonary edema
· Epigastric and right upper quadrant pain
· Grand mal seizures
· Intrauterine fetal growth restriction – often accompanied by ‘placental insufficiency’, abnormal fetal and maternal Doppler flow patterns (long discussion for another day!), and decreased amniotic fluid (oligohydramnios)

Specific subsets of severe preeclampsia, eclampsia and HELLP syndrome, are major contributors to the fetal and maternal morbidity and mortality that accompany the hypertensive disorders of pregnancy around the world. Eclampsia is defined as the new onset of grand mal seizures in a woman who meets the criteria for preeclampsia in the absence of any other neurologic disorder. This occurs in one of every 2000 pregnancies in the U.S. and in about one-third of cases does not occur until after delivery, usually within the first week postpartum, and sometimes as the first clinical manifestation of preeclampsia. The onset of seizures is often preceded by one or more of the following: severe headache, visual disturbances, irritability, epigastric, nausea, vomiting, and cerebral dysfunction. The cause of the seizures and other neurologic disturbances in eclampsia is at least in part a consequence of soft-tissue edema of the brain. It is prudent, however, if the woman has an atypical course of recovery from seizures, or doesn’t readily respond to therapy, that a more serious central nervous system complication (such as stroke, aneurysm, or tumor) is ruled out.

HELLP syndrome is one of the most interesting, enigmatic, and potentially serious manifestations of preeclampsia. It accounts for 10% or less of all cases of preeeclampsia and ranges in severity in different individuals. HELLP is an abbreviation for the laboratory abnormalities that define the condition: Hemolysis; Elevated Liver enzymes; and Low Platelets. The condition is characterized by intense vasospasm (contraction) of small blood vessels resulting in damage to the internal lining (microvascular endothelial cell damage) of these vessels and activation of the coagulation system(s) along the internal blood vessel walls as the result of the exposure of the thrombogenic (blood clot activating) factors that lie beneath the endothelium.

The hemolysis refers to the breakdown of red blood cells (RBCs) and this occurs in a pattern that is consistent with the RBCs being trapped and fragmented (microangiopathic hemolytic anemia) as they pass through these narrowed and damaged blood vessels in which the clotting system has been activated. The laboratory abnormalities reflect the RBC damage with abnormal appearance of the RBCs on peripheral smear (burr cells, schistocytes, spherocytes, triangular cells), and elevated levels of the RBC enzyme lactate dehydrogenase (LDH greater than 600 U/L) and serum total bilirubin (greater than 1.2 mg/dL) which results from the release and subsequent breakdown of hemoglobin from the RBCs.

The elevated liver enzymes are thought to result from damage to liver cells as the consequence of similar events. Liver transaminase (AST) levels that help to define the condition have to be greater than 70 U/L, but are often many times higher than this (sometimes in the 1000’s U/mL range). It should also be noted that the liver is an extremely vascular organ, and if significant damage occurs, intrahepatic hemorrhage, subcapsular hematoma formation, or even hepatic rupture may occur and can be life-threatening events even if recognized early.

The low platelets, or thrombocytopenia, associated with HELLP has been attributed to increased consumption and destruction of platelets at the sites of vascular endothelial damage where they are also ‘activated’ to clot by the tissues exposed beneath the blood vessel lining. Suspicion of HELLP syndrome is often raised when the platelet count falls below 150,000/mm3, but thrombocytopenia is not used to diagnose HELLP until the count is less than 100,000/mm3. In severe cases, platelet counts can be dangerously low, increasing the risk of hemorrhage during the cesarean sections that are often necessary due to fetal compromise accompanying the more severe forms of preeclampsia. HELLP syndrome, like eclampsia (and often accompanying eclampsia), may worsen or not be evident at all until after delivery in as many as one-third of women.

In our next post on this subject, we will discuss some of the risk factors for developing preeclampsia…

Labels: eclampsia, HELLP syndrome, preeclampsia

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Hypertensive Disorders in Pregnancy - 1

It’s been a BUSY week. I have been trying to keep up with responses to the many comments (and thank you for reading!), but haven’t had much time to provide new information! June is always hectic as the Chief Residents pack up their things to go and become incredibly hard to find, the 3rd year Residents start preparing to assume the role of Chiefs, the number of deliveries and the acuity of the patients start to peak, the interns begin arriving in town for their orientation, and the Faculty heads off on their summer vacations. Bad time to be a patient!

Earlier this week, I was asked to speak at a meeting that focused on the high fetal and infant mortality rates in one of our state perinatal regions. The goal was to identify risk factors and propose interventions that might begin to lower those rates which happen to be among the worst in the U.S. The postnatal factors that were most frequently associated with deaths of infants after delivery were found to be ‘sudden infant death syndrome (SIDS)’ and ‘unsafe sleeping practices.’ The tragedy is that many of these deaths are preventable and I will address those issues in a future post. The prenatal factors that were most strongly correlated with poor outcomes are pregnancy-induced hypertensive disorders and these were the subject of my discussion. Since summer seems to bring out the worst of these problems in the southeast, I thought it would be a good time to present a series to our readers on this topic.

Hypertensive disorders in pregnancy complicate 12-22% of all pregnancies. They are the second leading cause of maternal mortality, accounting for 17.6% of pregnancy-related deaths in the U.S. Worldwide, it is estimated that 75,000 maternal deaths are related to these conditions. They are also a leading factor contributing to premature deliveries and, in the U.S.; this translates to an average cost of about $50,000 per infant! About 70% of hypertensive complications in pregnancy are classified as ‘pregnancy-induced hypertensive’ disorders, sometimes referred to as ‘gestational hypertension’, but better categorized as a spectrum of conditions we lump under preeclampsia. About 30% of the complications are related to chronic hypertension with or without superimposed preeclampsia.

The definition we use for hypertension is a diastolic blood pressure greater than or equal 90mmHg or a systolic pressure greater than or equal 140mmHg and we generally do not label someone as ‘hypertensive’ unless the blood pressure (BP) is elevated on at least two occasions 6 or more hours apart. Of course, there are times when the BP is so abnormal that we break this rule! Chronic hypertension during pregnancy is usually defined as persistent hypertension from any cause that is present before 20 weeks gestation. Pregnancy-induced hypertension (PIH) is defined as the onset of hypertension after 20 weeks in a woman with previously normal BP. Occasionally, hypertension is truly PIH and found before 20 weeks and when this occurs it is often the result of abnormal placental tissues associated with either a ‘molar’ pregnancy, a chromosomally abnormal baby, severe isoimmunization, or congenital infection. And, when a woman shows up for her initial prenatal care for the first time after 20 weeks and is hypertensive, it can sometimes be difficult (at first) to decide whether this is PIH or simply chronic hypertension. Okay, now that we are clear on all that, in the next post, I will begin to address the diagnosis of preeclampsia during pregnancy…

Labels: Hypertension in pregnancy, PIH, preeclampsia

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Grand Rounds Thanks to Inside Surgery

Many thanks to the team at Inside Surgery for including my first (of three) posts related to the possible association of abnormalities in folate metabolism and methylation with risk for Down syndrome in Grand Rounds 3.37. My series on this subject was prompted by a patient who had that combination of problems. She had a history of recurrent early pregnancy loss, was found to be homozygous for the C677T methylenetetrahydofolate reductase polymorphism, and finally (after being placed on 'therapy') carried a baby that unexpectedly had Down syndrome (trisomy 21).

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Down Syndrome and Folate Metabolism - 3

In my last two posts (prompted by a query from Sheila, a woman who is homozygous for the MTHFR C677T polymorphism and had a baby with Down syndrome) we have tried to make a case for an association of abnormalities in folic acid/methylation metabolism and increased risk for having a baby with Down syndrome based on the worldwide medical literature. The overall sense is that such an association exists but that the expression of risk is variable and may depend on variations in genetic polymorphisms, geographical locations, dietary habits and perhaps other unknown factors. The presumption at the outset has been that these genetic polymorphisms increase the risk for Down syndrome by increasing (primarily) maternal risk for nondisjunction during meiosis. However, in my reading of the limited literature on this subject, it seems the actual cause may not be quite as simple as that and there may be other reasons we see more Down syndrome babies in mothers who carry these polymorphisms.

One of the first questions that should be asked under these circumstances is if these same metabolic abnormalities increase the risk for trisomies associated with nondisjunction of chromosomes other than chromosome 21. The only study I could find that addressed this issue was published in 2001 by Hassold and colleagues (Am J Hum Genet 2001;69:434-9). These investigators “analyzed maternal polymorphisms at MTHFR and MTRR in 93 cases of sex chromosome trisomy, 44 cases of trisomy 18, and 158 cases of autosomal trisomies 2, 7, 10, 13, 14, 15, 16, or 22, and compared the distributions of genotypes to those of control populations.” The only significant association they found was between the MTHFR polymorphism and the risk for having a trisomy 18 pregnancy.

Another intriguing area of inquiry is related to the survival and ultimate development of the Down syndrome conceptuses themselves. Most (80% or more) trisomy 21 babies do not survive the first trimester. We do not understand why some of these babies survive, and others do not, nor why some of these babies have severe malformations and/or mental deficiencies whereas others are not so profoundly affected. Could it be that these metabolic abnormalities of folic acid/methylation metabolism confer some ‘selective advantage’ to survival of these conceptuses? In other words, could there be a greater likelihood of survival among those babies that actually inherit these polymorphisms? If there is, then it might just appear that there is an association between maternal carrier status for these polymorphisms (that are very widespread in the population) and babies with Down syndrome.

At least one article might support this idea. In 2002, Hobbs and colleagues (Am J Med Genet 2002;113:9-14) examined the transmission frequencies of the C677T MTHFR polymorphism from heterozygous parents (parents that had both one ‘normal’ and one C677T allele) to their children with Down syndrome. They found that the C677T allele “was transmitted to children with Down syndrome (who survived pregnancy) at a significantly higher rate than would be expected based on Mendelian inheritance patterns…” Without going into detail, the authors hypothesized that the ‘beneficial effect’ of the MTHFR polymorphism might be in limiting the the ‘overactivity’ that results from 3 (rather than just two) copies of other folate-dependent enzymes whose genes reside on chromosome 21.

Of course, there is also the possibility that some of these babies do better simply because of better maternal nutritional status, which raises the prospects for improving outcome by folic acid and other supplementation. If you look back at my first post on this subject, Sheila was taking high doses of folic acid and other vitamins to help her achieve a successful pregnancy; her baby not only had no heart abnormalities, she apparently is doing quite well developmentally for a baby with Down Syndrome. With the well-documented benefit of folic acid in the reduction of neural tube defects, the growing evidence of the importance of folic acid in the development of the fetal heart, and the high prevalence of MTHFR and other folic acid/methylation polymorphisms among women in the general population, it appears we now have another good reason for insuring an adequate intake of folic acid prior to conception and during early pregnancy. If either (or both) the risk of having a baby with Down syndrome could be reduced, or the developmental outcome of these babies could be improved, by simply increasing the supplementation of folic acid in all reproductive age women, there could be a significant impact on pregnancy outcome and long-term costs of medical care.

Labels: Down syndrome, folate metabolism, folic acid, trisomy 21

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Down Syndrome and Folate Metabolism - 2

Since the publication of the first two studies cited in my last post related to this issue, various groups around the world have investigated the association of abnormalities in folate metabolism and methylation pathways and the risk for Down syndrome. Most studies have demonstrated such an association, although specific findings have differed based on the genetic polymorphisms studied and geographic locations of the study populations. Although these ‘inconsistencies’ might at first lead to doubts about the original findings, they probably can be explained by other differences in genetic backgrounds (geographic variations in types and combinations of polymorphisms) and even geographic differences in dietary habits that might alter the overall deleterious effects of the polymorphisms.

For example, we know that the most common gene mutation in MTHFR (C677T) does not completely inactivate the gene, but reduces its efficiency in catalyzing the biochemical reactions of importance. We also know that this deficiency can be overcome by supplementation with folic acid (hence ‘genetic predisposition’ and ‘environmental factors’) and greatly reduces the rates of neural tube defects. Therefore, women in parts of the world where the ‘usual’ diet is rich in folic acid may not necessarily demonstrate an association between MTHFR C677T and Down syndrome, although other genetic polymorphisms in these metabolic pathways, not readily overcome by folic acid alone, might still show a relationship.

Two studies from Italy illustrate my argument in this regard. In 2003, Stuppia and colleagues (Eur J Hum Genet 2003;11:5) reported that they found no significant difference in MTHFR C677T in 64 mothers of Down syndrome babies compared to 112 matched controls. However, a recent study by Scala, et al., (Genet Med 2006;8:409-16) presented a case-control study of seven polymorphisms of six genes involved in homocysteine/folate pathways and analyzed risks, not only of the single polymorphisms, but of combinations of these as well as well. They demonstrated significant associations between risk for Down syndrome and the presence of either another MTHFR polymorphism (1298C) or of the reduced-folate-carrier1 (RFC1) 80G gene. Furthermore, although carriers of the MTHFR C6777T polymorphism alone were not found to be at greater risk (supporting the earlier study by Stuppia, et al.), women who carried both the MTHFR C677T and 1298C were at significantly greater risk than those carrying either polymorphism alone. (Another recent study by Acacio, et al. (Prenat Diagn 2005;25:1196-9) from Brazil found women carrying the combination of these same two polymorphisms conferred a 5.7-fold risk for having a baby with Down syndrome).

Chadefaux-Vekemans and colleagues (Pediatr Res 2002;51:766-7) and Bosco, et al. (Am J Med Genet 2203;121:219-24) also found no increased risk associated with MTHFR C677T alone among French women and Sicilian women with Down syndrome babies, but let me remind you, the dietary habits of French, Italian, and Sicilian women, generally, include much higher intakes of folic acid rich foods than that of American women. And, interestingly enough, in the latter study, risk associations were found with both a polymorphism (MTR A2756G) in methionine synthase (3.5-fold risk), yet another enzyme involved in these metabolic pathways, and elevated homocysteine levels (6.7-fold risk). Women who carried both MTR A2756G and MTRR A66G were at 5-fold increased risk.

Other studies from around the world seem to support the association between abnormalities in folic acid/methylation metabolism and the risk for having a baby with Down syndrome, despite population variations. O’Leary and colleagues in Ireland (Am J Med Genet 2002;107:151-5) evaluated both the MTHFR C677T and the MTRR A66G polymorphisms among women who had Down syndrome babies in their country. They too found no correlation MTHFR C677T alone, but found a significant increase in risk in women who carried either one or two copies of the MTRR A66G polymorphism. Furthermore, women who had both the MTHFR C677T (one or two copies) and two copies of the MTRR A66G polymorphisms were at almost 3-fold risk for having a baby with Down syndrome. The only women who had elevated homocysteine levels were those who carried the MTHFR C677T polymorphism, so the increased risk associated with the MTRR A66G polymorphism did not seem to be reflected in the homocysteine levels of their study population. Rai, et al., (J Hum Genet 2006;51:278-83) in India found that women who were homozygous (carried two copies) for either the MTHFR C677T or A1298C polymorphisms had risks 7-fold and 4-fold, respectively, and in the case of the former, all the women who had a Down syndrome baby were less than 31 years of age. No such association between age and Down syndrome risk was found for carriers of MTHFR A1298C.

In my next post, I will wrap up this discussion with some other observations and thoughts related to aneuploidy risk and abnormalities of folic acid/ methylation metabolism and discuss the possible benefits of more widespread awareness of this association…

Labels: Down syndrome, folic acid

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