Michael Emerson, M.D. 2 I. Background of Biophysical Assessment A. Definition: multiple biophysical parameters are evaluated at a single setting 1. Dynamic a. Fetal heart rate (FHR): nonstress test (NST) b. Fetal breathing movements (FBM) (1) Incidence (2) Rate c. Fetal body movements (FM): incidence d. Fetal blood flow: Doppler velocimetry 2. Static a. Amniotic fluid volume (AFV) (1) Pockets (2) Quadrants b. Neurologic tone: flexion-extension c. Placental grade B. Significance of biophysical parameters 1. FHR: interrelationship of autonomic nervous system (ANS), acid-base balance, oxygenation, conduction, contract a. Clinical significance: standard tool assessing fetal- placental respiration, caloric reserves b. Baseline data (1) Rate (2) Variability (3) Response to stimuli (4) Periodic changes 2. FBMs a. Examples (1) Central respiratory regulation (2) Acid-base balance (3) Oxygenation (4) Neuromuscular integrity. (5) Maturity b. Clinical significance (1) Episodic (2) Related to time of day (3) Electrocortical state (4) Maternal fed state c. Baseline data (1) Incidence (percent time spent breathing) (2) Rate (3) Variability (4) Fetal body movements a. Examples The heart rate test was more likely to be abnormal first, decreased breathing activity next, decreased movement next and tone last. This exactly reflects the model that I gave you at the beginning so that our clinical observation of what goes wrong mirrors perfectly what was hypothesized in the model to be the way in which things disappear. It tells you that if your NST is your only abnormal component, and everything else is still pretty much intact, that the likelihood of significant hypoxia is small. If your NST and your fetal breathing activity are both either diminished or absent, your likelihood of hypoxia goes up substantially and if you add a third element, you might as well stop at the point because you have enough information to consider intervening on that baby. Let's go on to the issue of the fact that you could probably get away from having to do all of these variables and really you can eliminate movement, because once you get anything past breathing and NST your prognosis doesn't change whether you add movement or whether you add tone in terms of the likelihood of a compromised outcome. I am going to come back to tone because tone is our best window of anything that we look at into things occurring above the brainstem. Remember one of the things I mentioned in my previous talk that was a concern is that you can have a brain injury, unrecognized, the fetus recovers, survives and goes on and produces an apparently okay NST and may produce an okay AFV. How are you going to know that? The fact of the matter is that you may only know that by looking at fine motor activity of the fetus. You may only know that by watching the pattern of activity and the fact of making an observation that the fetus doesn't change state. So these are things that become more subtle. We are still a long way away from being able to reach this holy grail of predicting antenatal brain damage at the time that it occurs so that when they baby comes out and looks terrible and becomes a casualty that we are not consistently taken to task for doing something wrong during the process of labor and delivery. Again, if we take a look at management schemes, if we do testing, most of our testing is done on babies near term and if we have a normal test, this is a very robust statement of fetal condition, because we have the chronic component which is the amniotic fluid and we have the activity components. Together, that test can be robust enough to keep you in good stead for up to a week as opposed to the NST which is generally a two to three time a week exercise. If you did a perfectly normal biophysical profile and a patient's clinical status didn't change, then that could be good and be robust for you up to a week. If you have one abnormal parameter, it really depends on what it is. But in general, you want to look at the baby a little more closely and probably repeat that test to see whether you are dealing with a process in becoming, if that is a nonreactive NST, or if that is oligohydramnios. Again, amniotic fluid is not an absolute. You are allowed about a 10-20% variation in your AFI between the examination of sessions. The fetus urinates, the fetus swallows and so forth but you do want to look at the baby within 24 hours. Then, if you are still not satisfied, that is when you invoke your CST. That is when we most commonly invoke our CSTs. If you have two or more abnormal parameters, we look at that in a mature baby as being an indication to go ahead and deliver. In an immature baby, we would probably back that up with a CST. We want to be sure because we are looking at events that bear some relationship to fetal behavior that we are not looking at the possible influence of maternal medication. The maternal medications that are notorious for reducing the biophysical scores are medications that interfere with CNS function. Mag sulfate certainly is a classic. When you have babies on mag they just lie there because their mag levels get to the same level as their mother's. So if you want to know what the baby is doing, look at the mom. If she is lying back there, she can't watch her soap operas because she's got diplopia, she is groggy, sleepy, not moving around, the baby is doing the same thing. So when you are trying to evaluate babies whose mothers are receiving magnesium for preterm labor, for example, if you are doing biophysical assessment, that becomes a issue. It is a problem because you have blunted the things that you are 3 (1) Neuromuscular integrity (2) Oxygenation (3) Caloric reserves b. Clinical significance: rough measure of caloric homeo- stasis c. Baseline data (1) Incidence (percent time spent moving) (2) Numeric counts 4. AFV a. Examples (1) Aggregate of fetal urination (2) Gastrointestinal motility (3) Tracheal flow (4) Membrane exchange b. Clinical significance (1) Peaks at 34-36 weeks (2) Reflects visceral shunting in high-risk adaptions (3) Anomalies (4) Growth disturbances c. Baseline data: quantitative assessment (1) Pockets (2) Quadrants 5. Neurologic tone: reflex activity which may be elicited with sound or it may be spontaneous a. Clinical significance (1) Oxygenation (2) Central nervous system integrity (3) Motor function b. Baseline data (1) Flexion-extension (2) Attitude (3) Startle reflex (4) Sucking 6. Placental grade a. Morphologic description of placental maturity (senes- cence) b. Clinical significance (1) Crude estimate of placental aging (2) May be more advanced in disease states C. Concept of fetal states 1. Biophysical behavior is related at term to organized clusters called "states" a. State 1: quiet sleep b. State 2: rapid eye movement sleep c. State 3: intermediate looking for most carefully so then you are reduced to looking for issues that get very basic like are there late decelerations associated with contractions in this mother that you are tocolyzing? The standard score, as I mentioned to you, has five components in it. The thresholds for scoring these components are really, quite frankly, arbitrary. Generally, fetal breathing of more than 60 seconds would be reassuring under most circumstances. Movements, tone, AFV, or AFI and your NST. We use a modified scoring system that works out to 10 and 10 is a nice number. Eight and 10 are not necessarily equivalent because as I mentioned to you it depends on what you've lost points for. What happens when your score goes down is that you start this exponential increment in bad outcomes, whether it is antepartal death you can see here, there is no linear relationship at all. It just shoots right up there and your incidence of fetal distress and your incidence of neonatal depression are all elevated and you can make the same statement about babies that end up with abnormal neurologic outcome as a result of asphyxial injury. So there is a very, very sharp demarcation once you get to scores that are less than 6 and that should be regarded as being, again, a signal to intervene. Now let's get to the evidence. The evidence unfortunately is very limited. There really have only been a couple of trials that have compared the biophysical profile, the comprehensive profile, to the NST. The NST at that time was the gold standard. These are trials that are 10 years old. The numbers are not very large but what you see here, and this is actually not what the, I think, authors really wanted to show, but it is what in fact they have shown is that compared to the NST, the biophysical profile in these two studies doesn't appear to make a difference in your outcomes. Your perinatal deaths, your low Apgars, your intrapartal fetal distress cases were similar. I can say this because your confidence intervals include the number 1. Why is that? Why do you suppose that is the case? The reason that is the case is what you have done is you have taken a test which is part your biophysical profile, you set that off as your gold standard, and now you are comparing the rest of your biophysical profile to that test. Remember, in these centers the NST was done separately from the rest of the biophysical profiles so you could have tests in which the NST, had they been done together, would have been different than when they were done separately. But I would say that the overwhelming issue here is the numbers are far too small to make you feel comfortable that this is a definitive statement about how good the biophysical profile really is. I think the other issue here is that we probably won't get better control data than what I have shown here. There just isn't money to do the studies. The NICHD isn't interested funding that kind of work anymore and so we are going to have to take it on faith that what I have told you physiologically makes a lot of sense. If you understand the components and what they are trying to tell you and interpret the differences between the chronic and acute components and remember that the test is not perfect, it gives you more information than does any single component. I think at that point what we are seeing here is the fact that this is the best case scenario we are going to have. This doesn't stop me from doing biophysical profiles but it makes me very careful in terms of interpreting the biophysical profile as a single stand alone test. Let's talk about umbilical flow velocimetry and let's put this into a location where you can take something away that might be helpful for your practice. The story of Doppler really goes back now a decade and a half so it is not really news but I think if we take a look at the cord. Let's look at the circulation that we are dealing with and why this is a very interesting part of the fetal circulatory system. Again, I promised I would give you a little bit of physiology here because I think it makes you better consumers to understand what the label means rather than just going ahead and buying the product. Here, actually, is the part of the circulation that we are interested in and it is way, way downstream but here are the umbilical arteries. As you know, the umbilical arteries course along either side of the 4 d. State 4: "wakefulness" (active) 2. State influences a. Time of day: circadian rhythms b. Maternal diet status, oxygenation c. Maternal drugs d. Gestational age III. Technique of Biophysical assessment A. Instrumentation 1. Electronic FHR monitor a. Doppler b. Air encephalogram (AECG) 2. Realtime ultrasound (US) B. Test conditions 1. Standardized for a. Time of day b. Maternal status c. Length of observation 2. Concurrent acquisition of biophysical IV.Test Interpretation A. "Standard" biophysical profile: 1. Sequential NST and US 2. NST: two or more accelerations >15 beats per minute (bpm) in 20 minutes 3. Realtime scan a. FBM: >30 seconds of continuous breathing b. FM: >3 movements c. Fetal tone: >1 flexion-extension episode d. AFV: one pocket of 10 mm x 10 mm e. Placement grade <3 4. Overall test requires 25-70 minutes 5. Scoring system a. Each parameter ranges from 0 (abnormal) to 2 (normal) b. Total score >8 is normal; <4 is abnormal B. Alternative approach 1. Concurrent recording of all parameters under standardized conditions 2. Data relaxed to institutional normal values 3. Value >two standard deviations from normal: abnormal 4. Test performed for 60 minutes 5. Normal test: all parameters normal 6. Abnormal test equals two or more of the parameters abnormal PR decline >50% bladder and eventually join the central circulation and are tributaries off the iliac, the aorta and receive a fairly downstream blood flow from the main pump up here. Here you see the umbilical vein going back up and getting admixed with the enterohepatic circulation. Eventually that oxygenated blood enters the right atrium where it encounters a current coming from the superior vena cava. So what the arterial circulation of the umbilical cord really is doing is it is the last tributary to bring blood back to the placenta for processing. So it has an obviously very important physiologic role because the placenta is a surrogate lung, it is a surrogate GI system, it is a surrogate kidney and it acts as a way of dealing with the acquiring of essential nutrients, substrates, oxygen and the detoxification of the blood by getting rid of CO 2 and hydrogen ions and broken down metabolites from substrates that have already been processed. Now, if we take a look at the developmental basis for velocimetry, we know that after the mid trimester, placental adaptation generally is fixed in terms of the number of cotyledons, the number of central vessels that exist on the chorionic plate. The main change that occurs in the placental circulation of the fetus is a large increase in terminal villus units or the so- called microvasculature of the placenta. Physiologically, this is a system that is adapted to give you a low resistance to flow in its terminal end. Abnormal resistance to umbilical blood flow then is a process that suggests that something is going wrong, either by infarction of this vascular tree or by perhaps initially a hypoplastic situation where you don't get this great proliferation of vessels to great quantities. Experimentally, abnormal systolic/diastolic patterns, which I will show you shortly, can be created with placental infarction and this has been done successfully in laboratory animals through embolization. So you can recreate this by destroying selectively parts of your placenta. You can recreate this increased resistance to flow that you get in a compromised baby. In addition, pathologic examination of the placenta has shown a very good correlation between terminal villus capillary counts and the waveform patterns that are seen, again, in disturbed pregnancies. The nice thing about looking at the umbilical vessels is that it is easy and 96% of the time you've got two shots at getting one. They are easy to identify. They are easy to see. They have long courses and this is just recapitulation of what I have already told you, but the fact of the matter is why pick a target that is hard to find? Part of the appeal also is the fact that this is a circulation that is very stable. Under situations where there is chronic hypoxemia, we have preservation and actually an increase in blood flow to the placenta which is your umbilical arterial circulation, the brain and the heart and you can see under a chronic hypoxemia - the white boxes - that everything else is diminished. This tells you how well adapted the fetal circulatory system is to environmental stress resulting in chronic hypoxemia. If we take a look at the Doppler examination itself, again it is a very simple technique and that has really been part of the appeal because you can do it in an office. The technology now for operating the Doppler equipment is really very simple and it has been made even simpler because it has onboard computers. It is the same technology that we have used for years to just capture fetal heart rate. It is just specially adapted to both an auditory and visual display that captures the waveform that is unique to the umbilical arterial circulation. I can take anybody from scratch who has never done it before and make them experts in about 20 minutes. The probes here are standardized, generally operating at about 3.5 MHz, and we get a nice display screen. When we use the continuous wave, which are the cheaper, more mobile machines, we generally take a look at the cord with a real time ultrasound before so we pick a part of the cord that is neither near the beginning, near the egress of the cord from the abdomen, nor near the end where it is implanted into the chorionic plate. Because in that intervening space it makes relatively little difference where you intersect the artery when you are doing repetitive examinations. 5 V. Summary of Previous Clinical Experience A. Benefits 1. Improved detection of anomalies, intrauterine growth retardation (IUGR) cord problems 2. Diagnosis of neuromuscular, neurologic problems 3. Two or more abnormal parameters appear to increase sensitivity 4. Corroboration of abnormal fetal acid-base. B. Drawbacks 1. Placental grade: not useful 2. Fetal breathing affected by a. Diet b. Labor c. Time of day 3. Tone: questionable benefit 4. AFV: no standards 5. Time-consuming, labor intensive, expensive 6. Not proven superior to FHR testing with or without AFV assessment VII. Doppler Velocimetry A. Fetal-placental circulation 1. The fetal umbilical-placental circulation a. Anatomy (1) The fetal cardiovascular system is characterized by a relatively high output, low pressure/low resistance network which oxygen delivery is regulated (2) Blood flow is phasic and influenced by (a) Cardiac cycle: systole and diastole, which provide two surges; the direction of flow is rate-dependent (b) Afterload: increases with peak systolic flow and decreases with peak diastolic flow (c) Breathing: increased tracheal pressure in- creases venous forward flow and umbilical vein pulsations b. Umbilical vessels (1) Two arteries (a) One to two millimeters in diameter anastomosing at chorionic plate (b) The number of cotyledons and three orders of branches are constant after 14-16 weeks (c) Growth results from proliferation of terminal syncytial budding stemming form capillary plexus which protect villi from blood pressure If we are going to be more sophisticated and use a continuous viewing system, the so-called duplex Doppler system that you have in most of your mainframe ultrasound machines, then there are a couple of issues that become critical. One is your scanning angle or angle of insonation. The advantage of this, of course, is that you can see your waveform unequivo- cally as you are scanning your vessels so you know that you are not looking at something else. But I can tell you as well that the data that you get from this approach are very, very similar to those that you get from a good continuous wave machine that is well aimed. I throw this in here. We have color and I am sure many of you have color also. Is there an advantage in using color in terms of insonating the umbilical arteries? I would submit to you that it unequivocally tells you that you are looking at arteries well, maybe that is going to be an issue it certainly is helpful when you are dealing with babies that are oligohydramniotic. So it helps you visualize the cord and aim your Doppler probe better. It is not absolutely necessary and you can effectively do this kind of insonation without having color. Again, what you are doing with either approach is you are sending a beam into a moving stream of red cells. These red cells will send you back a reflection that is at a slightly different frequency. There is a shift. You hear it. It is the "whoosh-whoosh" that you hear. That is the difference in Doppler signal going in and reflective signal coming back. It is processed by your machine and then it is displayed on the screen. The display on the screen, the so-called waveform, is really a Fourier transformation of zillions of data points that are all reflected by these populations of red cells that are moving in different directions at different speeds. You could never deal with this on a three-dimensional plot. It would look like a mountain range so it is reduced to two dimensions by Fourier transformation. There are different ways of dealing with the waveform. Most of the schemes use a peak. Either a peak to trough, the so-called S/D ratio or a peak to mean velocity. A peak to mean velocity is the so-called pulsatility index. There are advantages and disadvantages to both approaches. They convey similar information. The only advantage of using the pulsatility index is when you have either an absent or a reverse end diastolic velocity, you can still get a number. Not that it is necessarily important if you ever have an absent or a reverse end diastolic velocity. We generally take a number of cycles. We sample them. We average them and this reduces the likelihood that the fluctuation you see from session to session is going to be just due to an observational technique issue. We do at least three repetitions. We take about 15 cycles and then we pool them, average them and come up with our results. Our onboard computer, of course, gives you the PI. It gives you also, I should mention, the resistance index because you will see this in some publications. It is the peak less trough over the peak. Again, PI and S/D and RI all convey similar types of information. They are not really apples and oranges. If we take a look then at clinical interpretation, which is really sort of the big payoff here, what is the clinical interpretation? What do we get from that? You are going to get a number. Obstetricians are enamored of numbers. We have Apgar scores, we have Bishop's score, we have the breech score, we have various pelvic scores. I mean, we really love numbers and this is a number so we should love it. But we have to understand how to use it and what it really means. What it really means is nothing unless you have a scale of reference in which to apply the number that you get. If you don't have that then all that you have is a number. There are times when that is not necessary and there are times where you have abnormalities of your end diastolic flow. Remember that it should always be a positive waveform in diastole and the only time that the positive waveform disappears are under circumstances of extremely increased downstream resistance. Depending on degree, it may disappear or it may appear on the other side of the x-axis. In addition, we look at this clinically in sequence over time because this is not a static observation. It is a moving target. If we take a look at here at 6 (BP) changes (2) Intervillous pressure: 10-15 mm Hg (3) Umbilical arterial pressure equals fetal systemic pressure (4) Umbilical blood flow (a) Peaks at midgestation (b) Resistance falls by 3% per day (c) Blood flow decreases in proportion to fetal weight c. Control of umbilical flow (1) No feedback system for pressure or resistance, not directly affected by hypoxia (2) Not innervated beyond first 2 cm proximal (3) Constricted by vasoactive agents (a) Prostanoids (b) Angiotensin-II (c) Bradykinins (d) Vasoconstriction leads to increased O 2 extraction (4) Flow rate (a) Determined by systemic perfusion pressure difference (A-V) (b) Responds to changes in i. FHR ii. Stroke volume iii. Cardiac contractility d. Responses to stress (1) Acute hypoxia: redistribution or cardiac output leads to decreased umbilical blood flow to de- crease in cardiac output which leads to venous return (2) Chronic hypoxemia: restricted placental growth leads to decreased capillary bed size; terminal resistance does not fall or may increase C. Clinical manifestations of vascular flow 1. Determinants of volume flow a. Vessel diameter and wall thickness b. Vessel linearity and uniformity (distensibility) c. Turbulence: transmission and reflection d. Blood volume properties (1) Density (2) Viscosity (3) Cell morphology e. Applied pressure (1) Pulsatility what is known for normal pregnancy, and we now have a lot of data on normal pregnancy, basically over time there is a decline in the overall trend of the S/D ratio or pulsatility index as the fetus becomes more mature. The reason for that is really very simple. Over time as the placenta increases in size, your downstream vasculature continues to grow and you continue to reduce your downstream resistance. If you take a look at a waveform, and this is just one graph. There is an S/D ratio that however old the fetus is going to be distinctly abnormal and that is an S/D ratio over 4. From that point forward, an abnormal S/D ratio is really going to depend on where you are in gestation and that is an important point. Because as you get closer to term, at 40 weeks, if you have an S/D ratio that is over 3, that is an abnormal ratio. It would not be an abnormal S/D ratio, say, at 30 weeks. You can see here there is a pretty broad spread between these are the 5th and 95th percentiles so that again gestational age trends and there are few absolutes unless you are greater than 4 or at term, if you are greater than 3. Now let's look at what happens as we start losing the integrity of the fetal- placental circulation. You start getting a gradual widening between peak and trough until we get down towards the bottom here. You can see that the trough almost has disappeared and then at the bottom we see the trough appears on the other side of the x-axis. So this is a progression from normal to absent end diastolic and finally to reverse end diastolic velocity. You very rarely see this evolve over single pregnancy because the absent or reverse end diastolic velocity in and of itself is a very uncommon finding. If we take a look, even without numbers, if you take a look at two waveforms on the same scale, you don't have to have numbers to tell you that this looks a lot different from this. This baby has a normal S/D ratio of about 2.5 and this baby has an S/D ratio that is about 5. How did we do that? We took the peak, we took the trough and we did a ratio. Simple. This is actually done for you. You might be able to see on the machine here, you actually have these computers for you on board so there is no processing you have to do yourself. Here is an absent end diastolic velocity and here is one in which the end diastolic velocity appears on the other side of the x- axis. Where is the payoff for this particular technology? The payoff is really limited but there is an area in which I think it makes sense to consider adding Doppler to your armamentarium. That is in the situation where you have a pregnancy that is either thought to be growth restricted or has a very high probability based on maternal disease or past history or lifestyle of being a growth restricted pregnancy. The reason that we pick this is the clinical studies that have been done so far suggest that the yield is very high in this particular subgroup. Further, there is a collection of pathologic observations that have looked at the placentas of these babies and have correlated placental morphology with Doppler velocimetry. Remember, IUGR is not a pure population. It is a spectrum and you may have IUGR in which the baby is asymmetrically poorly grown in which the head generally is relatively spared, the body is not and then you have the symmetrically IUGR baby where everything is small. This is generally the asymmetrics are the ones that appear later in pregnancy, the symmetrics earlier and remember that the symmetrics are the ones that are more likely to have other very serious problems - chromosomal problems, infections and other malformations. The interesting thing here is because you are looking at a developmental process in the placenta, what you are observing here is that the waveforms on sequential Doppler velocimetry of the umbilical vasculature may start appearing to be abnormal before you have any other evidence to support that this baby is having trouble growing or adapting to an intrauterine environment. The general lead time can be as much as several weeks so that if had a situation, if you had a pregnancy in which you thought that here is a high-risk for IUGR, mom is hypertensive or has advanced diabetes, wouldn't it be nice to get a heads up on things that are going to be going 7 (2) Amplitude f. Peripheral resistance 2. Characteristics of fetal-placental vasculature a. Small diameters, thin walls b. Short length, nonlinear, easily distended c. Numerous branch points: angle turbulence d. Differences in maternal and fetal blood e. Pulsatile flow related to rate and systemic pressure f. Low resistance systems 3. Semiquantitative measurements of circulation a. Empirical indices of flow velocity (1) A:B (S/D) ratio: f(max): systolic peak/f(min): diastolic peak (2) Pulsatility index (PI): f(max) - f(min)/f(mean) (3) Pourcelot's ratio (resistance index): f(max) - f(min)/f(max) (4) Frequency index profile: median of peak/mean during cycle D. Doppler studies of normal and complicated pregnancies 1. Normal pregnancies a. Waveforms are characterized by high flows with low resistance b. Curves generated across pregnancy are similar for systolic/diastolic (S/D) ratio, pulsatility index (1) Slope changes at 28 and 36 weeks (2) Variation inversely proportional to gestational length c. No significant effect with changes in viscosity either at high shear (RBC aggregates broken up) or low shear (RBCs clumped) d. No significant relationship to umbilical venous flow 2. Intrauterine growth retardation a. High sensitivity and consistent finding of elevated flow resistance indices b. Worst prognosis associated with absent or reversed end-diastolic flows c. Highly predictive or placental pathology d. Histology: obliterated or reduced terminal arterioles in villi e. Separate population of IUGR fetuses with anomalies had normal S/D ratios, indicating nonplacental source of problem f. Waveform indices may be elevated weeks to months prior to clinical diagnosis of IUGR. This sign is typi- cally, the first abnormal sign in testing schemes wrong downstream so that you can start looking at the baby more closely? That is certainly something that has been observed by a number of authors that have looked at the application of Doppler to this population. The other area in which there has been some value in the use of Doppler have been twins. I am not going to belabor that point. You had a very nice talk on twin pregnancy before. But the fact of the matter is that twins are more prone to having growth disturbances. They are more prone to having abnormalities of placental circulation to begin with and discordance between twins and discrepant fetal growth are the hallmarks of twin gestations. We have altered the distribution of twins in our population by assisted reproduc- tive technologies so we are seeing more of them and certainly of the areas where one could apply Doppler, this area makes sense. Again, this is sort of an extreme example. I know these babies are the same age because I saw them when they born although they don't look like they are at all related. Here you have this nice robust twin over here and then you've got his little brother over here who really doesn't look quite so healthy. Here is another parable of Doppler done in twin pregnancy. This is the parable of the good girl and the bad boy. Over here you see twin 1. Nice normal Doppler velocimetry, nice heart rate tracing. On the right, you've got twin 2. Absent end diastolic velocity, sort of a nonreactive trace here. Here you can see the graph of twin 2. The bad boy who never has normal Dopplers in the third trimester and the good girl's whose Dopplers are always within the normal range and so you go ahead and deliver these babies. You sort of split the difference and deliver them at about 34 weeks and the good girl weighs 2,000 grams and the bad boy weighs 1,000 grams. The point here is as an adjunct to measure to supporting your hypothesis that the placenta is not functioning well in a discordant growth that again Doppler has a role in twin gestation. As a sole screening modality for fetal well being in the third trimester, Doppler is very limited. Again, I show you this slide for the NSTs. Here is the same basic slide for Doppler. The big four. Postdates, diabetes, IUGR and hypertension. Not surprisingly, the only populations in which Doppler appears to have potentially assisted detection of compromise have been the IUGR and the hypertensive group and you can see that is really below 50% sensitivity here. In the diabetic group and in the postdates group it is relatively useless. The only exception in the diabetic group are those who have advanced diabetes with vascular complications. So we don't do it all in our postdate pregnancies. We long ago abandoned using Doppler in that group and we focus on the hypertensive, IUGR and multi-fetal gestations. In closing the session on Doppler, I have to tell you the reason that I spent time on this subject is that Doppler is the best studied from the standpoint of evidence and outcomes based of all of the modalities that I have shared with you this morning. There have been about a dozen trials in the past decade that have been reported in Europe looking at umbilical Doppler. Nine included only high risk patients which I think really is the province of this particular investigation. If we take a look again of this table of outcomes here, if you look at all of the outcomes and this is all of the trials pooled together, what you see here for the most part is that if you look at general populations, there appear to be no advantages in using Doppler. If we focus on perinatal death, this is now getting into the general population, perinatal death as an endpoint, what you see here in the area of most importance is stillbirth because that is something we can do something about potentially by antepartal surveillance, you can see that we are starting to make a dent. In fact, the application of Doppler as part of the surveillance in the high risk populations resulted in a 38% decrease in stillbirth and this contributed to about a 33% fall in overall perinatal death and this was significant. You see this confidence interval falls below 1. If we focus only on high risk pregnancies, which is the true province, it is even more dramatic. You can see here that perinatal mortality falls by 50% or greater for stillbirths in the population in which Doppler was used as part of the screening modality. If we take this to heart, what we can we really take away from this? First of all, these were not trials done in the United States so you could attribute 8 3. Multiple gestation (twins) a. Clinical concerns (1) Relative IUGR after 28-29 weeks (2) Twin-twin transfusion syndrome b. Methodology (1) Realtime scan to locate individual cords (2) Values are similar to singletons except when IUGR is present (3) Twin-twin transfusion syndrome characterized by size disparity with equivalent S/D ratios c. Study results: S/D ratio differences of >0.4 associated with IUGR 4. Diabetes mellitus a. Few data reported indicates that, regardless of size-for-dates classification, elevated S/D ratio sug- gests an arrest of fetal growth over time b. Elevated S/D ratios are also associated with higher incidence of perinatal complications 5. Normal labor a. Fleischer et al in 1987 studied twelve normal parturients (1) No significant differences in S/D ratios during any phase of uterine contraction (2) No differences noted between latent phase, active phase, after rupture of membranes, or with administration of oxytocin b. Smart et al in 1981 studied ten normal patients with similar findings 6. Postdatism a. Recent ,data suggest that S/D ratio may be a good predictor of perinatal morbidity in this population b. S/D ratio is not reflective of oligohydramnios 7. Establish relationship of velocity parameters to clinical conditions E. Conclusions 1. Doppler waveform analysis is a relatively new application which can be performed with moderately priced equipment 2. The semiquantitative measurement of velocity waveforms are now generated by current hardware, and are relatively reproducible throughout gestation 3. Doppler information can be obtained rapidly by easily trained personnel 4. The usefulness of Doppler measurements of fetal umbilical vessels remains to be established but shows promise in the evaluation of fetuses at risk for IUGR this to different forms of antenatal care. They were trials that are done very close to our particular era of practice. That in addition, we could either say that we refuse to believe this because it wasn't done in a U.S. center or we can say that perhaps there is something to the addition of Doppler to selected high risk populations. That, in fact, that if we are to really call it like it is, let's now put our collective thoughts together and perhaps retrace where we have gone this morning before I open this up to general questions once again. What are we really trying to accomplish with antepartal testing? We are really trying to prevent stillbirth, but preventing stillbirth due to possible preventable causes and what is the major preventable cause is preventable perinatal asphyxia. So I am backing this up because really if we had a good way of reliably reproducibly measuring health so that we could confidently say that asphyxia is either present, the risk of asphyxia is either highly present or highly absent, that would be a giant step forward. A relatively accessible testing scheme which uses clinical features that we can get our hands around to identify fetuses at such high risk that labor should be avoided and perhaps early intervention should be encouraged. Translating that possibly into model systems to even improve our ability to forecast intrapartum outcomes before the onset of active labor. Because you know that the intrapartum area is where a number of unforeseen problems might occur. Now, if we take a look at antepartal testing, if accelerations are present, the likelihood of not having an asphyxiated baby is pretty high. If accelerations are absent and persistently absent, the likelihood of having a baby that is affected by hypoxemia or acidemia is almost as high but not quite as high. If we look at heart rate variability, as measured objectively by computer, not by the eyeball, normal variability, again, very low likelihood of asphyxia. Certainly not zero and if variability is abnormal or absent, again, very high. Decelerations the same story. So what you see here with antepartal heart rate testing is that, again, normal or abnormal antepartal heart rate testing alone approaches the target but you can see that you have to be willing to accept a significant error. I would call an error of 15-20% in calling a baby well and an error of 30-40% in calling a baby ill a significant error. Because it means that you are going to intervene much more likely on a baby that is going to be well on the one hand and you are going to miss babies that you should have delivered. Now let's look at biophysical profile testing. If you look at biophysical profile testing, if you have a score of less than 8, there was a 90% sensitivity in positive predictive value for asphyxia. This was a selected population delivered without labor. If you look at Manning's study, looking at the correlation of biophysical profile with cordocentesis for blood gases done at the same time, there is a stepwise linear relationship between biophysical score and umbilical venous pH. If you look at a computerized biophysical profile that we do in cord blood gases, there is a linear relationship between score and ultimate umbilical artery pH at delivery. So again, it suggests that biophysical profile testing by multiple components moves you a step closer to making a good assessment for the absence or presence of asphyxia without either over or undercalling the situation. If we look at Doppler velocimetry, again, as a sole predictor, this varies a lot from study to study but the bottom line here is that as a sole predictor, that again, is no better than any of the other isolated tests that we do. Again, these are based principally on high risk populations. You might ask yourself, "Gee. What does a 40% likelihood of hypoxia do for me?" I can assure you if somebody told me that this baby has a 40% likelihood of getting hypoxia, that would get my attention. We intervene for likelihood of compromise far, far lower than that in our obstetric practice. That would get my attention. 9 The markers for perinatal asphyxia, conventional testing, trying to use what we currently have to predict it consistently or sufficiently early really have problems. I am being very honest with you because part of my career has really been in this area. I am saying that we have to understand that there are limitations in trying to go after this target. When we look at studies, remember that we are looking at studies that are all population based and the populations, even though I have melded them together to give you these meta-analyses, the populations may tend to be somewhat different from each other. My population, I know, is different from yours. They don't talk the same way. Their lifestyles are different and therefore the findings from one state might not be generalizable to another. In reality, there should be a lot more work done in this area. Even though it has been around for two decades or more, some of the real seminal basic work that should have been done has not been done and that is a pity. But I think that also gives us an opportunity here to look at where we should go. These are areas that we are working at and other centers are working at to give us a better handle on how to best assess babies. I happen to be an advocate of the computer approach because I think that deals with a lot of number crunching that is very hard to do with pencil and paper. But also there is context. We should really approach this issue of perinatal assessment trying to uncover the risk in these babies and we should do it really with the knowledge that we already know a lot about each pregnancy, or we should. We should know a lot about the antecedent risk factors. We should know a lot about that patient's prior history. We should know a lot about her current state of health and the things that are really putting this baby at risk. Those invariably should reflect on how we interpret the data and how we use it. That again means that you do have to do some individualization. There is, again, little question that if you get your hands on a high risk pregnancy early, then you are able to establish early the baseline age of this pregnancy through good ultrasound, rule out anomalies through good ultrasound. Make an assessment of where you are starting from, again, with good ultrasound, and using that as your backbone, you will end up with a better scheme for prospectively following this baby. I am not dismissing the possibility that as we get further into the information age, that some of this assessment could be translated into a home environment. So in other words, we could take patients that we don't want to have doing a lot of running around, we can bring technology to their homes through home visits, through telemetry, bring it back to us and make it actually more convenient for our patients. I know that is probably more difficult to do in Chicago where you have weather. We don't have that problem. We just have a fairly difficult road structure to deal with. But that is again something that I am sure is going to happen progressively more and more in the future.