Amniotic Fluid - 5 - Evaluation and Management of Oligohydramnios

Just as the fetal outcome depends on the degree, underlying cause, timing during development and longevity of decreased amniotic fluid, to some extent, so do the management options. When the baby has complete absence of both kidneys (bilateral renal agenesis), or absence of functional kidneys (bilateral multicystic or polycystic renal dysplasia), and no amniotic fluid, then as we pointed out yesterday, the fetal outcome is clear – the condition (Potter’s sequence) is lethal. Since this outcome is inevitable, regardless of the gestational age at delivery, interruption of the pregnancy is a reasonable option if the patient wishes to proceed with that. When I trained, that was considered to be a reasonable option at any gestational age as well (whenever the patient was ready to proceed) and, in my mind, it still should be, however, there are many individuals and state regulations that consider this a ‘pregnancy termination’ and practitioners are reluctant to perform labor inductions in such women beyond the gestational age at which the state limits such procedures. Unfortunately, this might require a woman to carry her nonviable baby for 4-5 months after she has been given the diagnosis.

Another option under these circumstances is to offer the patient a program of ‘fetal hospice care.’ The goal of such programs is to allow women and their families the opportunity to spend as much time with the baby, before and after birth, as possible. We structure this with frequent office and ultrasound visits (for those who prefer) and ongoing counseling before and after delivery. In addition, we try to identify other families who have been through the same or a similar situation as a means of additional support. We will often identify one physician to lead the care of the pregnancy, avoid unnecessary testing and interventions, try to create a sensitive birth experience without fetal monitoring and with experienced nursing staff, have a neonatologist available to rapidly confirm the baby’s status following delivery, and allow the patient and any family members she welcomes to be present at the delivery to spend as much time with the baby as possible after birth. Although this approach is not for everyone, those that go through with it are almost always rewarded by the experience.

Less clear is the management of the ‘obstructive uropathies’ that are accompanied by reduced amniotic fluid and, indeed, discussion is beyond the scope of what we need to present herein. In brief, management and outcome depends on when in pregnancy the obstruction is detected and the extent of residual kidney function. As an example, if one is fortunate enough to detect an over-distended bladder and oligohydramnios as the result of posterior urethral valves (bladder out let obstruction) very early in pregnancy, there is the option to place a bladder shunt, diverting urine from the bladder into the space around the baby. Theoretically, this might help reduce the risk of pulmonary hypoplasia. However, the fetal outcome under these circumstances is highly variable. Sometimes the kidneys and the bladder have been too damaged by the obstruction to recover, sometimes the shunts have to be replaced repeatedly, and sometimes the babies still develop abdomens that remain distended and poorly muscularized as the result of the over-distention during critical stages of development – a condition called ‘prune belly syndrome' – and/or respiratory insufficiency. Complete, bilateral ureteral obstructions (between the kidneys and the bladder) are even more of a challenge, but fortunately these are very rare.

Management of premature rupture of membranes (PROM) also depends to a large extent on the timing in pregnancy. If this occurs prior to 20 (or even 22) weeks, the risk of fetal complications related to pulmonary hypoplasia and fetal deformations and the risks of maternal complications secondary to infection are so high that many practitioners will simply advise their patients to undergo pregnancy termination. Unfortunately, for counseling purposes, the outcome under these circumstances can be difficult to predict, particularly if the baby is able to maintain, even intermittently, a small amount of fluid within the uterine cavity. But it is likely that less than 5% of babies with PROM before 20 weeks have any chance at all of intact survivial.

For the patient who is reluctant to undergo pregnancy termination, an option is to simply counsel regarding risks and signs of infection (and the absolute necessity of proceeding with delivery once infection is suspected) and to follow the pregnancy over time. After initial stabilization and evaluation in the hospital, we offer most of these women outpatient management. Other than counseling there is no more that can be offered except perhaps antibiotics. There is no standard of care in the use of antibiotics under these circumstances (in fact some would decry it) but after several unexpectedly good outcomes under these circumstances, I have gotten into the routine of beginning, empirically, a broad spectrum IV cephalosporin antibiotic or penicillin to cover Group B Streptococcus, pending results of cervical-vaginal and urine cultures, as well as a 5-day course of azithromycin, and prolonged prophylactic therapy with metronidazole (the latter being given orally until delivery). Once the baby reaches the point of potential viability, hospitalization can be considered, if the patient desires more aggressive fetal surveillance.

Management of PPROM after viability has been obtained usually involves hospitalization from the outset, careful assessment for infection (even to the extent of including amniocentesis to evaluate the fluid around the baby for evidence of infection and inflammatory markers) and ongoing fetal monitoring to try to balance the risks and benefits of continuing intrauterine management versus delivery. Again, this topic is best suited for another entire post alone.

One of the more challenging, and more common, situations involving the management of pregnancies with reduced amniotic fluid is in the setting of ‘placental insufficiency’ that usually is the late culmination of abnormalities of placentation that occurred very early in pregnancy. As we discussed in our last post, when babies are not getting enough across the placenta to meet metabolic demands and to maintain normal patterns of symmetrical growth, they are able to ‘redistribute’ blood flow to essential organs such as the brain and heart. One sign that this is occurring is progressive growth of the fetal head out of proportion to that of the abdomen – asymmetrical fetal growth restriction. Eventually a critical stage is reached at which point so much blood flow is diverted away from the nonessential organs such as the kidneys, that fetal urine production drops and subsequently the amniotic fluid volume, placing the baby at risk for both cord compromise and too little oxygen. When babies truly start to become unhappy in these situations, it is not uncommon for their mothers to develop hypertensive complications of pregnancy (preeclampsia) and these frequently accompany intrauterine growth restriction.

One of the most effective means we have of ascertaining that these blood flow changes are occurring, sometimes even before significant growth abnormalities have taken place, is Doppler flow velocimetry. This is a noninvasive ultrasound-based technique that allows us to measure resistance to flow (and at times velocity of the flow) in blood vessels. In normal pregnancies, resistance to blood flow from the baby to the placenta as measured in the umbilical arteries is usually very low – indeed, blood normally continues to flow to the placenta even between beats (end diastole) of the fetal heart. At the same time, under normal conditions, resistance to blood flow to the fetal brain (usually measured in the middle cerebral artery, or MCA) is usually high. Though this resistance often decreases as pregnancy progresses, resistance to intracranial blood flow should always exceed resistance indices found in the umbilical arteries. In contrast, when there is decreased resistance in the MCA, this suggests fetal blood flow redistribution and it is often accompanied by increased resistance in the umbilical arteries reflecting the abnormalities in placentation (invasion of the maternal spiral arterioles) that led the pregnancy to this point. When the resistance in the MCA actually falls below that found in the umbilical arteries, the baby may well be at a critical stage requiring delivery, regardless of the gestational age.

When we follow the pregnancy with reduced amniotic fluid, there is not necessarily going to be a single test that tells us the baby is better off out than in. It is one of those situations where we may have to use several of the antepartum testing modalities – nonstress test (NST), contraction stress test (CST), biophysical profile (BPP), and Doppler flow velocimetry - we have at our disposal to aid in the decision-making process. This is especially important when there are complications related to oligohydramnios in the very premature baby. There are many times when the maternal condition must be factored into the decisions as well, particularly, when there is evidence of preeclampsia accompanying intrauterine fetal growth restriction associated with placental insufficiency. One must also be very cautious in the pregnancy with placental insufficiency because the baby often has had time to adapt to the chronic stress of its environment and can often appear better off than it really is even just before decompensating completely.

This concludes an overview of the pregnancy with decreased amniotic fluid. I apologize if I over-simplified some aspects of this discussion, but I wanted to present the information in a way that most of our readers could grasp the basic concepts. In the next post we will begin a discussion of increased amniotic fluid – polyhydramnios (or, simply hydramnios)...

Labels: Doppler flow velocimetry, oligohydramnios, preeclampsia, premature rupture of membranes

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Plasminogen Activator Inhibitor-1 (PAI-1): Role in Adverse Pregnancy Outcome? - 2 - Late Pregnancy Complications

In our last post, we discussed the role of plasminogen activator inhibitor-1 (PAI-1) in helping to maintain the balance between the clotting and fibrinolytic (clot-dissolving) sides of the coagulation system. The primary function of PAI-1 is to inhibit plasminogen activators (t-PA and u-PA) from converting plasminogen to plasmin which is responsible for initiating fibrinolysis. The premise is that if there is too much PAI-1 activity, clots will tend to hang around longer and if there is too little, the individual would be at increased risk for bleeding problems. Before we can address possible roles of abnormalities of PAI-1 production and activity in adverse pregnancy outcome and recurrent pregnancy loss (RPL), it would be helpful to understand changes that might occur in these parameters during normal pregnancy.

Kruithof and colleagues (Blood 1987;69:460-6) reported that both plasminogen activators (t-PA and u-PA) and plasminogen activator inhibitors increased during pregnancy. t-PA and u-PA increased 50% and 200%, respectively, throughout normal pregnancy. They also found that PAI-1, produced predominantly by endothelial cells lining blood vessels, increased nearly 10-fold by term over that found in nonpregnant women and a second plasminogen activator inhibitor, PAI-2, not found in nonpregnant women, but produced by the placenta, was present in very high concentrations by term. The increase in both activators and inhibitors appeared to maintain the balance between the clotting and fibrinolytic systems during normal pregnancy because no changes in plasminogen or the overall fibrinolytic activity were found. Within “three to five days after delivery most parameters of the fibrinolytic system were normal again.”

In 1989, Estelles and colleagues (Blood 1989;74:1332-8) reported that women with severe preeclampsia in third trimester had significantly higher levels of PAI-1 than nonhypertensive women. Interestingly, PAI-2 levels were significantly lower in the preeclamptic women and a positive correlation between birth weight and PAI-2 levels was found (in other words, the higher the PAI-2, the greater the birth weight); and birth weight was inversely correlated with PAI-1 levels (higher the PAI-1 activity, the lower the birth weight). The presumption is that the lower PAI-2 levels correlated with a decreased placental mass or function in preeclamptic women. Regardless, the high levels of PAI activity in severe preeclampsia appear to be solely related to the increased activity of PAI-1. And, as many of our readers are aware, this might account in part for the coagulation abnormalities frequently accompanying the more severe forms of preeclampsia.

Unfortunately, these observations late in pregnancy don’t really tell us whether elevated levels of PAI-1 in preeclampsia are a cause, an effect, a response, or a contributor to the disease process itself. Based on several observations by other investigators, and the putative role of PAI-1 in placentation early in pregnancy (which we will eventually get to here), perhaps it is all the above. There does appear to be a genetic predisposition/association with abnormalities in PAI-1 production and later pregnancy complications. Yamada and colleagues (J Hum Genet 2000;45:138-41) evaluated the association between preeclampsia and deletion/insertion polymorphisms (4G or 5G) in the promoter of the PAI-1 gene. The 4G/5G polymorphism was assessed in 115 women with preeclampsia, 210 normotensive pregnant women and 298 nonpregnant controls. The frequency of the 4G allele (which results in increased production of PAI-1) and of 4G/4G homozygosity was significantly higher in the preeclamptic women than either the normal pregnant or nonpregnant controls, suggesting that the presence of 4G is one risk factor for preeclampsia and perhaps more severe manifestations of the disease.

Along the same lines, Glueck, et al. (Metabolism 2000;49:845-52) evaluated complications in 133 women with at least one pregnancy, and found a significant association of the 4G/4G PAI-1 polymorphism with prematurity, intrauterine growth restriction (IUGR), and “total complications of pregnancy” that was independent of the presence of other genetic thrombophilias (factor V Leiden, MTHFR C677T, and prothrombin G20210A mutations). In a subsequent study (Glueck, et al., Obstet Gynecol 2001;97:44-8), they reaffirmed the presence of the 4G/4G genotype as a risk factor for IUGR and extended their findings to include associations with severe preeclampsia, placental abruption, and stillbirth. They also reported that “the hypofibrinolytic 4G/4G mutation of the PAI-1 gene…is frequently associated with the thrombophilic factor V Leiden mutation” which would further increase the risk of problems related to clotting.

Over the years, PAI-1 made by vascular endothelial cells was found to be induced by angiotensin II which is produced by the action of the angiotensin I-converting enzyme (ACE). In a fascinating paper published in 2003, Xia and colleagues (J Soc Gynecol Invest 2003;10:82-93) reported that 18 of 20 women with severe preeclampsia were found to have IgG antibodies to the angiotensin II type 1 (AT1) receptor. None of 18 normotensive pregnant women had these autoantibodies. They also found that the serum from the same 18 of 20 women with these AT1 receptor autoantibodies stimulated PAI-1 secretion by trophoblasts (placental cells) in culture. Activation of the trophoblast AT1 receptors was also correlated with decreased trophoblast migration and invasion in tissue culture models and this, too, was directly correlated with PAI-1 production. We will return to this point in our subsequent discussion of the role of PAI-1 in recurrent early pregnancy loss. Bobst and colleagues (Am J Hypertens 2005;18:330-6) further reported that AT1 receptor autoantibodies found in preeclamptic patients stimulated PAI-1 (and the cytokine IL-6) production by human kidney (mesangial) cells in culture. Reversible ‘damage’ to the kidney is one of the events which characterize preeclampsia and the more severe the kidney impairment, generally, the more severe the preeclampsia with regard to hypertension and decreased urine production...(more to follow!)...

Labels: IUGR, PAI-1, preeclampsia, thrombophilias

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Two First Trimester Miscarriages

Labels: maternal age, miscarriage, preeclampsia

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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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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 - 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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