Dr. Ernst has disclosed that she does not have any real or perceived conflicts of interest in making this presentation.
Star Legacy Foundation Rep: On behalf of the Star Legacy Foundation staff, our families, and our babies gone too soon, we honor all of the families and their children we have served throughout the years. It is our privilege to present Dr. Linda Ernst. Dr. Ernst is currently an Associate Clinical Professor and the director of Perinatal Pathology at NorthShore University HealthSystem. She is board certified in Anatomic Pathology, Clinical Pathology and Pediatric Pathology having trained at Yale University for her residency and the Children’s Hospital of Philadelphia for fellowship.
She has devoted her career to Perinatal Pathology with clinical expertise in Placental Pathology and Perinatal Autopsy. One of her greatest contributions to the field is the beautiful Color Atlas of Human Fetal and Neonatal Histology. She has also had an active research career with over 90 peer-reviewed publications on subjects related to fetal and placental pathology. She is currently the Vice Chair for Research in her department, and a co-investigator on 3 NIH-funded research projects to evaluate the importance of placental pathology in poor pregnancy outcomes. Welcome, Dr. Ernst.
Dr. Linda Ernst: Hello. My name is Linda Ernst, and today I’m going to be talking about the value of pathologic examination in stillbirth. Just as a warning, this presentation will have some sensitive information and some photos from autopsies. I’ll show this sign a few more times to warn you. I don’t have any relevant financial disclosures.
As an outline of my talk, we’ll start by a little bit of background on the problem of stillbirth. Then we’ll talk about the pathologic evaluation of stillbirth, why we do it, how we do it, and how we classify cause of death. Then at the end of the talk, I’ll go through a few important topics that I’ve seen commonly as a perinatal pathologist when evaluating stillbirth.
First, a definition of stillbirth. Delivery of a fetus showing no signs of life, meaning no fetal heart rate, no pulsations of the cord, no breathing movements or other voluntary movements. In the United States, the reporting of stillbirth is not completely uniform, but most states report stillbirths at 20 weeks or greater. It’s a pretty common problem occurring in 1 to 160 deliveries in the United States. That signifies more than 20,000 stillbirths a year in the US.
There are some known risk factors for stillbirth, and those are listed here in a table from the most recent ACOG bulletin on stillbirth. You can see that if you have diabetes, if you have hypertension, preeclampsia, if the fetus is growth restricted, if there’s a multiple gestation pregnancy, if you have chronic diseases like lupus or renal disease, if you’re a black race, and if you’re obese, you have increased rates of stillbirth.
I also like this table because it’s from data from longer ago, from 2005, but you can see that there are certain conditions like lupus and renal disease, as we said, that have a higher odds of stillbirth. I think it’s important to say that the prevalence of stillbirth is highest at 80% amongst low risk pregnancies. In most cases, there’s not a disease that gives you a risk for stillbirth in the mom and it’s an unexpected event. Stillbirth is a common problem and most stillbirths do occur in low risk pregnancies.
The goal of my talk today is to tell you what the essential components of a stillbirth evaluation are. This question has really been answered in the literature via a multicentered prospective study and the most important tests that have come out to be relevant are a full autopsy and placental examination, a cytogenetic analysis, and testing for fetal maternal hemorrhage. Amongst these even four tests, the autopsy and placental exam are recognized as the most important tests in the evaluation of stillbirth.
Again, from the most recent ACOG bulletin, you can see here, they have a roadmap of how you should approach a stillbirth, the fetus and placenta should be inspected, and you should obtain consent for cytogenetic testing. An attempt should be made to obtain consent for an autopsy in all cases and autopsy and placental exam should be done in all cases. If an autopsy can’t be done, we’ll talk a little bit about some other techniques that could be used.
They also talk about working up the case based on the clinical scenario, and you can see, depending on the clinical scenario across the top here, what testing should be done and no matter what the clinical scenario is, all end in doing a fetal autopsy and placental exam, because those two tests are the most important. You can see that genetic testing is also relevant in many of these scenarios as well as testing for fetal maternal hemorrhage.
The fetal autopsy, as we said, is a very important test, but it’s also an unusual laboratory test in that it requires patient consent. In this case, it would be parental consent. Everywhere you work, there will be a consent form for autopsy. This is what ours looks like at NorthShore. I think the relevant things to point out are that the parents have to give consent for a complete autopsy, or they can restrict the autopsy in whatever way they choose, and it does require of the parent and a witness.
Not all parents do agree to have an autopsy and not all parents are even asked if they would like to have an autopsy. There are many reasons why stillbirths aren’t all investigated by autopsy, even though we’ve already said it’s the most important test. For families, there may be religious or cultural beliefs that prevent them from consenting to an autopsy. They may not understand the autopsy process and don’t understand what it is or what the benefits are, and they may fear disfigurement of the body. I’ve heard people say they don’t want their baby cut, or their baby has suffered enough.
For clinicians, sometimes there’s an idea since we had an ultrasound or other imaging prenatally, we already know what happened. They may be ignorant of the benefits of an autopsy. They may not understand the process and fear explaining it to their patients. They may fear litigation, and they may be cost conscious.
Overall, pathologists play a role as well. There has been a general decline in autopsy rates over many years, and it’s really an undervalued exam compared to all the other work that pathologists do in surgical pathology. Many pathologists are not well trained in autopsy. In fact, the American Board of Pathology just reduced the number of autopsies needed to sit for the board exam. I also think there’s this erroneous idea that the small size of a fetus should make it faster and easier to do, and in fact, that’s not necessarily true.
What can we do to combat all these things that are getting in the way of us getting autopsies done in stillbirth? I think that the answer is education. That providers who have a discomfort with the consent process, they must learn about the process, be able to explain it, learn the value of it so they can tell their patients about what it will do for them. It’s good to know about the options besides autopsy, including other virtual techniques and or how this autopsy might interfere or not interfere with funeral arrangements. It’s also very good to know about the cost of an autopsy.
I know this is an overwhelming amount of information to know when maybe this happens as a clinician to you once every few years. That’s why pathologists are here, and I suggest if you are considering an autopsy, really, it’s a consultation with a pathologist and you shouldn’t hesitate to contact them and discuss the case, discuss how to ask for consent, discuss your specific concerns.
At my place, I worked with the palliative care group to actually make a document that was intended for patients, but I think it also helps the clinicians as well of a frequently asked questions about autopsy. It was meant to be the flip side of the autopsy consent form, and it could be run through with the patient as they’re looking at the consent. It answers the questions of, what is an autopsy? When do you need it? How do you request one? Who performs an autopsy? What’s the cost of an autopsy? Does it interfere with funeral arrangements? How long does it take to get the reports and how do they get the results? I’m happy to share this with anybody who’s interested in a document form.
Once consent for autopsy is obtained, this is kind of the roadmap of how an autopsy is done, and I’m just going to go through informing you about what does happen in an autopsy. If you need to know it to explain it to your patients, you will have this information. We start here with obtaining consent. The remains of the fetus are taken to the morgue, and then to the autopsy suite for the examination. The autopsy is performed and that is typically performed with a pathologist and perhaps where you are a resident pathologist as well, who’s training.
We usually do it as soon as possible after death, as soon as we’ve obtained the consent. In many places on the weekends. We try to talk to the clinician. Even if they haven’t reached out to us, we’ll try to reach out and make sure we understand the questions. That will begin the exam with radiographs, photographs and the full examination, which includes making incisions, doing an evisceration of the organs, dissecting out all the organs and sampling the tissues. This is a several hour process that we go through on the day that we do the autopsy.
Then within two days, we’ll generate a provisional report. Then in the time after that, we’ll be looking at microscopic slides that we’ve made, doing a literature review, coming to inclusion about the report, and a final report we’ll be generated. Just to go back here. After we finish on the day of the autopsy, the incisions are closed, the remains of the fetus are returned to the morgue, and then the fetus is released for hospital or private disposition.
A little more detail about the examination. Our examination always includes photographs and radiographs, and then we do all kinds of measurements to document the growth of the fetus, the overall appearance and looking for any external anomalies. We document any maceration changes related to retention in utero after fetal death. If need be, we will take a skin sample for cytogenetics.
Just as an aside, I do recommend that the sample for cytogenetics be taken as soon as possible after delivery. Oftentimes, by the time we get the autopsy, it’s not the best sample. At our place, it’s done in the delivery room, mostly from the placenta.
Just warning, I’m going to show some photos of how we actually do the autopsy, just a few here. It’s important to see how the incision is made so you can explain that to your patients. This is the incision. It’s a Y incision on the skin, and you can see it can be easily closed. The baby can be clothed, and none of the incisions will show.
From that incision, we will open up and do an internal examination of all the organs. The first thing we’ll try to do if we need it is cultures before we contaminate any of the field. If the case calls for it, we’ll do cultures, we can do blood spleen or lung tissue. Then we’re doing a thorough inside to examination of the chest, of the abdomen, of the neck, of the thorax, everything before we remove the entire organ block and separate all the organs and weigh and measure everything.
The other incision that’s made is to remove the brain in addition to that Y incision. That is a U-shaped incision over the top of the head, which again, can be closed up and a baby’s head on a pillow that incision should not be seen. Once we reflect the skin back, we can open the skull bones and remove the brain.
As I said, after we finish that dissection, this is the gross examination. I put the googly eyes there because it’s what we see with our eyes, not with the microscope. You’ll get an initial report of what we saw with our eyes. You can see a lot with your eyes. We can tell you a statement about growth and maturation, we can tell you if there’s anomalies, we can tell you if there’s evidence of infection and we can tell you about the placenta. This is, as I said, within two working days of the dissection.
Then the microscopic exam, obviously using the microscope, will really be looking at every organ. We submit the tissue in tissue blocks and then that gets turned into glass slides, which we can look at under the microscope. From that examination, we’ll come up with the final diagnoses, we’ll summarize the clinical course, we’ll give a description of the gross and microscopic findings. Then we try to put it all together, correlating what we see under the microscope and grossly with the clinical findings, the laboratory findings, any culture results and genetic studies will be incorporated into the report.
Just, again, to reiterate, this was the map and this was the day of the autopsy and then the microscopic exam and everything else was in this part of the final part of the autopsy.
A few other important things that I think should be included because they’re not really part of the roadmap is that historically autopsies free of charge to a patient at the hospital. This may vary by institutions. Most institutions that I’ve ever worked at provide autopsy as part of quality improvement, but you should know your own hospital’s policies. If your hospital, for instance, is referring autopsies out to an expert or regional center, there may be a cost. Generally, an autopsy does not interfere with an open casket funeral, as I showed you with the incisions and it should not delay funeral arrangements.
Genetic testing was also one of those important tests that I mentioned and it’s recommended in stillbirth to rule out aneuploidy, and it seems the favored technologies now are microarray and NGS, because they have a higher yield of finding a causative abnormality in stillbirth. I think this literature will continue to grow as we uncover more and more genetic abnormalities in stillbirth.
The placental exam is also a very important part of a fetal autopsy. It’s actually an important part of stillbirth examination even when fetal autopsy has been declined because in many cases cause of death can be defined by the placenta alone and things like placental infarction, umbilical cord abnormalities, ascending intrauterine infection, abruption et cetera can be identified in the placenta, and it’s definitely an adjunct to the autopsy findings.
Here’s the summary of what information can be provided by the pathologic examination in stillbirth. You can document fetal growth, you can document any major or minor anomalies, correlate that with genetic testing, we can document maceration, infection, any changes with acute or chronic hypoxia. We can add in the placental pathology and give an overall statement about cause of death.
Cause of death in stillbirth, generally, the definition is an injury or disease responsible for death. Specifically in stillbirth, I like this definition. An event or condition of sufficient severity, magnitude, and duration for death to be expected in the majority of cases in a continued pregnancy in the clinical setting where it was observed.
I think what this brings in is severity and magnitude and duration, because I have this frequently asked question, “How can you say, for instance, an umbilical cord knot was the cause of death when you can see umbilical cord knots in live babies?” The answer is, it has to be of sufficient severity, magnitude and duration, and I have to be able to demonstrate that. We’ll talk a little bit about that coming up.
Unfortunately, many of these classifications are one cause of death, but oftentimes there are multiple consequences that come together to ultimately be fatal for a fetus.
I think it’s important to recognize that even with a full autopsy and placental exam, anywhere from 25 to 60% of cases may not have an explained cause of death. But I think if you flip that around, a key point is that we can determine cause of death up to 75% of the time and that can be extremely helpful.
In terms of classifying cause of death, there are many classification systems and none that are universally accepted and I’ve just thrown up a few of them here. You can see they’re generally organized by large categories like anomalies, infection, maternal disorders, you see placental disorders and all of them have an unclassified or unexplained at the bottom as well.
My favorite one is this one. It’s called the initial causes of fetal death or in CoD. I like it because it– this is the front page of the coding sheet. It talks about conditions as either being present, being possible, or being a probable cause of death. Obviously possible is there’s a possibility it’s involved in the pathologic sequence and probable there’s a high likelihood. For those where there’s multiple findings, it’s helpful to put them in either the possible or probable categories. Of course they do divide it into these seven major categories, maternal medical, obstetric, hematologic, genetic, placental and fetal infection, and then placental conditions.
We took this coding system and applied it in a stepwise fashion to see what did the placental pathology and autopsy exam add to cause of death. First, we just examined the clinical data and coded the case. Then we added the placental pathology and coded the case and then coded the case if it had an autopsy based on all three.
Here’s the data showing that when we started off with the clinical data alone, you can see that a probable cause of death was only identified in 25% or so, and more than half of the cases really had an unknown cause of death. When we added in the placental pathology, this probable cause of death jumped up over 60%. The possible was up higher too. With the full placental and autopsy exam, we were up around 75% with a probable cause of death and no case remained completely unexplained at this point.
Also, what about beyond cause of death? Is there any other information to be gained in terms of counseling for next pregnancy or how you’ll manage the next pregnancy? Does it change the attitude of the patient, et cetera? Our data showed that it was helpful in terms of how the pregnancy was managed the next time in terms of either doing additional growth scan, counseling regarding recurrence risk, et cetera.
There’s another study as well done in the Wisconsin Stillbirth Collaborative, where they had over a thousand stillbirths and this pie graph showed the different changes that an autopsy diagnosis meant in the subsequent pregnancy in terms of recurrence risk, counseling, preconception management, prenatal diagnosis, et cetera.
Some of the challenges with autopsy is that we have to educate providers of the need, we have to educate the patients and families of the need, we have to talk about cost, we have to talk about pathologist expertise and transportation of remains. What about limitations on the autopsy or other non-invasive techniques for autopsy? By giving talks like this, I’m hoping that we can educate providers and hopefully patients and ultimately patients and family about some of these challenges.
In terms of what other choices are there besides an autopsy, the non-invasive fetal examination is becoming more popular. This is essentially the use of radiologic techniques to examine fetuses postmortem. This includes CT scans, MRIs, and ultrasound. You could think of this as a virtual autopsy and combat some of these issues of family concerns over body disfigurement.
Most studies have been done using MRI and compare them with the gold standard or the conventional autopsy, and you can see accuracy ranges from 77 to 94%. They’re somewhat comparable in their ability to detect abnormalities. MRIs, really, best for brain anomalies, which are difficult at conventional autopsy because of the softness of the brain tissue. CT scan also has been done a little less sensitive and ultrasound also can add things, but has less accuracy.
A major criticism of these non-invasive techniques is that histology isn’t done. Some people have incorporated selected biopsies with these virtual autopsies. One of my major concerns is this needs collaboration between pathology and radiology. It’s not simply a pathology test anymore, and it’s not simply a radiology test anymore, so we have to work together.
In the last few minutes, I would like to just talk about a few things that I think are important when you’re evaluating a stillbirth. My three themes are pay attention to the umbilical cord, placental insufficiency, and the pale fetus. Of course I’m going to be showing some pictures here, so I just wanted to warn you. Pay attention to the umbilical cord. This is a really important message. The umbilical cord is the conduit between the fetus and placenta and all kinds of things can go wrong with that connection, and essentially that’s the blood supply to the fetus. Things like knots, long umbilical cords, nuchal cords, hyper coiled cords, all these things can potentially lead to abnormal delivery of blood to the fetus.
Umbilical cord problems do become more of a problem in later gestations. This is some work I never published, but that cord issues were quite common above 24 weeks. And much less common in the younger gestational ages.
In that same study where we did the stepwise evaluation, you can see here, these two groups that I’ve circled in red are the groups that have cord problems and probable cord accident, if you will. That was over half of the placental causes of death in our group. Over half of the placental causes. What’s happening in this kind of a situation is that there’s a stoppage of blood flow at the umbilical cord level, and this affects flow to the umbilical vessels, the chorionic vessels on the chorionic plate, and the deeper stem vessels within the placenta.
Ultimately, that blood has to get to the capillaries and go back to the fetus, and if there’s some obstruction anywhere in the system, that stops blood flow. What we see when that happens is thrombosis in these vessels and we see death of the villi or vascular villi and villous stromal-vascular karyorrhexis in the deep parenchyma.
That looks like this with thrombosis of the fetal vessels on the chorionic plate here, and when we look at it microscopically, we confirm these are thrombi made mostly of fibrin in chorionic and here occluding the stem villus vessels.
Avascular villi is the deeper change, and here you can see an area here that’s completely lost its blood supply and high power. What this looks like is villi that have all their intervillous space fine, because this is all mom circulation, but the inside of them has lost their vessels. Normal here, and you can see no vessels here. A close up, you just see fibrotic sclerotic villi with no capillaries. In areas adjacent, you might see capillaries. In fact, you might see an abundance of capillaries, a compensatory hyper capitalization, and even some nucleated erythrocytes in those capillaries suggesting hypoxic stress.
How does this actually lead to fetal death or morbidity? Well, one you’re losing a fair area of perfusion. Two, this increases vascular resistance through the placenta, and these damaged vessels can release factors that are detrimental to the fetus. Also, once you thrombose in the placental circulation, you have the chance to embolize and that could be, for instance, directly to the brain through the fetal shunts, ductus arteriosus, and foramen ovale.
Umbilical cord coiling has always been one of my favorite topics. Normal coiling is 1 to 3 coils per 10 centimeters. It’s been associated with some fetal abnormalities and it has a fairly high prevalence amongst examined placentas. Coiling can be either right or left. 75% are left and about 25 right. I started noticing these very coiled and almost sausage like links between the coils that were really indented in the cord.
I started seeing this a lot in stillbirth and really wanted to look at it. I defined these four patterns. These first two being the undulated and rope with very little indentation of the cord between the coils and the segmented and linked with more deep indentations, and found that those segmented and linked patterns are much more associated with thrombi in the fetal vasculature, avascular villi, and stillbirth in general. Interestingly, the right coiling pattern is also more associated with all those findings in including stillbirth.
Pay attention to the umbilical cord. It’s a common and underrecognized cause of death in stillbirth. When you have an abnormal cord or cord insertion, you must look to demonstrate evidence of obstruction in the placenta. You need thrombi and avascular villi to blame the death on cord accident.
That’s me running out of time. I’m just going to run through quickly. Placental insufficiency is my second key point. Placental insufficiency really in this case is resulting from multiple placental infarcts or maternal vascular malperfusion which will decrease the nutrition to the fetus. You can see here what you’re doing is obstructing the maternal blood flow to the placenta, which will histologically show some vascular lesions and some secondary villous lesions.
Here are some of the vascular lesions with fibrinoid necrosis and artherosis. The villous lesions include distal villous hypoplasia and increased perivillous fiber deposition.
When you do an autopsy on a baby with severe placental insufficiency, you may see an SGA baby. You usually don’t find anomalies or infection, but you do see signs in the fetal organs of hypoxic stress. Again, amongst the placental causes of death, this was seen in almost 20% of our stillborn in that study.
Then lastly, the pale fetus. Sometimes you come to the autopsy suite and you see a very pale fetus, a very pale placenta. When you look at the liver, you’ll see increased extramedullary hematopoiesis. The bone marrow also may show erythroid hyperplasia. The placenta can be edematous, and show a lot of nucleated reds. These are the kind of findings that suggest fetal maternal hemorrhage, especially at gross exam, if you see a very pale fetus, almost no intravascular blood when you’re doing the case, and placental pallor, make sure that they have done testing for fetal maternal hemorrhage.
Although it’s recommended, it’s not always done, and it’s really the definitive way to say its fetal maternal hemorrhage. In this case that I’m showing you, there was almost 40 mls of fetal blood in the maternal circulation, which was a significant percentage of the fetal blood volume and massive fetal maternal hemorrhage was the cause of death in that case.
That’s my perspective on those three major topics in stillbirth. I hope today I’ve been able to talk to you about the value and convince you of the value of the pathologic examination in stillbirth. Thank you.
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