Causes of Unexplained Pregnancy Loss

June 29, 2021
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Harvey J. KLIMAN, MD, PhDAfter bereavement support following a pregnancy loss, the next most important step is to
determine the cause of the loss. This can both start the healing process and potentially help prevent future losses. Unfortunately, current pregnancy loss classification systems leave far too many cases unexplained. It is uniformly acknowledged that placental pathology plays a key role in understanding pregnancy loss. Therefore, we examined the placental pathology in a cohort of 385 previously unexplained stillbirths from 20-43 weeks gestational age that had been sent to a consultation service at Yale University School of Medicine.

Harvey J. Kliman is an MD, PhD graduate in Medicine and Cellular Biochemistry from the University of Chicago. He is currently a Research Scientist in the Department of Obstetrics and Gynecology, Yale University School of Medicine, and the Director of the Reproductive and Placental Research Unit with a special interest in infertility and pregnancy complications. He has over ten patents, including the “Method and system for determining placental volume.” In addition to his research and teaching activities at Yale, he also consults with doctors, patients and lawyers to evaluate complicated cases of unexplained infertility, pregnancy loss, and poor pregnancy outcomes.

Dr. Kliman has disclosed that he does not have any real or perceived conflicts of interest in making this presentation.

Nidhi Shah: Hi, everyone. I’m Nidhi Shah from the San Francisco Bay Area Chapter of the Star Legacy Foundation. I became involved with the foundation after our son Kian was stillborn at 41 weeks in December of 2019. Thank you, Star Legacy Foundation, for always being our support system and for bringing us all together here today.

Next up is Dr. Harvey J. Kliman. Dr. Kliman is an MD, PhD graduate in Medicine and Cellular Biochemistry from the University of Chicago. He is currently a Research Scientist in the Department of Obstetrics and Gynecology, Yale University School of Medicine, and the Director of the Reproductive and Placental Research Unit with a special interest in infertility and pregnancy complications. He has over 10 patents, including the “Method and system for determining placental volume.” In addition to his research and teaching activities at Yale, he also consults with doctors, patients and lawyers to evaluate complicated cases of unexplained infertility, pregnancy loss, and poor pregnancy outcomes. Over to you, Dr. Kliman.

Dr. Harvey J. Kliman: This is Harvey Kliman from the Yale University School of Medicine. I’d like to first express my sincerest condolences to any mother or family who has suffered pregnancy loss. Today I’m going to be talking about causes of unexplained pregnancy loss, and hopefully ways to prevent them in the future when possible.

I’d like to start off by sharing the story of one of my patients, MM. MM at the time was a 25-year-old who was 36 weeks and 4 days. When she went to see her doctor, her blood pressure was a little elevated at 142/83. They said, “You need to watch out for certain things that might indicate that you might be developing preeclampsia.” They told her what those things were. A few days later at 37 weeks and 2 days, she actually did develop those signs and symptoms. She had headaches, visual spots, and edema for a day.

She came back to her doctor’s office and her blood pressure was elevated at 135/98. They asked her to go to labor and delivery. By the time she got there, her blood pressure had actually gone down, but they still looked at her urine to see if there was protein in her urine. That’s a test for preeclampsia. They also did something called a non-stress test, an NST.

What is an NST? An NST is basically looking at the fetal heart rate on the top panel here and also the contractions of the uterus at the same time. Every time there’s a contraction of the uterus, and I’m showing you one right here, there should be an elevation in the fetal heart rate. If that happens, then it’s read as a normal NST. She had a normal NST, so she was sent home.

She complained of decreased fetal movement at 38 weeks and 3 days. She came back to labor and delivery. They did another NST, it was normal. They sent her home, but they said, “Why don’t you come back in about a week, and let’s just make sure everything is okay?” She did. She came back exactly a week later at 39 weeks and 3 days. They did another NST and it was normal, and they sent her home. Unfortunately, the next day at 39 weeks and 4 days, she had no fetal movement. She presented to labor and delivery with a stillbirth. This is a horrible tragic event for anybody.

One of the first questions a mother always has is, “Why did my baby die?” And then the next question always seems to be, “Is it my fault?” I just want to say right now, it’s not the mother’s fault for this to happen. Where can we get the answer? “Does it have something to do with my body?” She might be thinking. “Might it have something to do with the uterus? Maybe there was something wrong with my baby.” What I’d like to share with you is that the answer is usually always found in looking at the placenta.

Now, let me tell you a little bit about the placenta. A lot of people don’t understand that the placenta is part of the baby, part of the fetus. Here’s a diagram of a fetus connected to its placenta, and you can think of the placenta as like the roots of the tree. When we look at a tree above ground, we see the tree trunk, the branches and the leaves, but underground, there is as much of a tree in the root system as there is above ground.

The same thing is true in pregnancy. The placenta is part of the fetus biologically, genetically, physiologically. The fetus pumps blood through its umbilical cord into its placenta where it gets all the nutrients, oxygen, food, energy, gives up its waste products through the placenta. The fetus is completely dependent on its survival by the placenta.

You can see that the placenta does sort of look like a root system in this diagram. The fetus would be up here connected to its placenta through its umbilical cord, the blood vessels branch through the top part of the placenta, and dive down to form the root system here. The muscle layer of mom, the uterus is here. The lining of the uterus is here, and mom sends her blood into the placenta, into something called the intervillous space and the fingers basically of the placenta would be like you putting your hand in a bucket of water is how the nutrients from mom’s blood to the fetal circulation exchanges through these fingers of the root system. The placenta is absolutely critical for supporting a fetus during pregnancy.

When we looked at placentas of unexplained pregnancy loss, between 4 and 43 weeks, we were able to find the answer to these pregnancy losses in the majority of cases by looking at the placenta in great detail. We usually divide up the names of pregnancy loss as the different types, based on the gestational age. Of the 1,262 cases we looked at, we first looked at the cases that were less than 20 weeks. We call those miscarriages. Miscarriages in our country, there are about 1 million a year. We examined 878 of these, and these, as I said before, were previously unexplained. They had been looked at at other places, but they still couldn’t figure out the answer.

They sent them to me and my laboratory at Yale to try to figure out why these pregnancy losses occurred. When we examined the placentas, we found that basically 86% of the cases had abnormal development, something genetically abnormal with them here, the blue part of the pie chart here, and a much smaller fraction about 2% had clotting disorders or some immunologic problem, the pink and the olive segments right there. In about 12% of the cases, the green part of the pie, we actually couldn’t figure out the exact answer for why the loss had occurred.

When we looked at pregnancies that losses occurred at or greater than 20 weeks, we call those stillbirths, and we examined a number of those. Let me just define a stillbirth in terms of the frequency. It occurs about 25,000 a year in our country or 6 per 1000 in the United States. We looked at 384 stillbirth placentas that were previously unexplained. When we examine the placentas in detail, we were able to get the answer in about 99% of the time. You can see the pie chart on the left, the different percentages.

Here’s the key of what the different causes were, and I’d like to walk through the different causes of what we found in these pregnancy losses. The most frequent cause of stillbirth was a small placenta. 131 cases, or exactly a third at 33.3%. This is the most common cause of stillbirth, a small placenta. Why are placenta small? We looked at the details of the different causes for these small placentas. And this is shown on this chart and you can see that still the majority are due to this blue shading area, which is due to a genetic abnormality. That was the most frequent cause.

The next most frequent was decreased maternal blood flow into the placenta itself, and then maternal immunologic rejection where the mother’s immune system actually views the placenta as foreign and attacks it, and then a small percentage of the time, the green band right here, we couldn’t actually find the answer. Still in the majority of cases, we’re able to do it almost 99% of the time.

Now, what is the definition of a small placenta? The usual definition is a placenta that’s less than a 10th percentile. If you look at the whole population of all the placentas born at any gestational age, you can make a bell-shaped curve as shown in this next figure. The pink bell-shaped curve is the normal distribution of weights of placentas at different gestational ages. This is actually a standard deviation chart with zero being the exact average, that’s why the peak is right here. Then the numbers either below or above are standard deviations above and below that. Just for reference, the dotted lines, the dashed lines I should say, are representing the 90th percentile here and the 10th percentile here.

Normally, when you look at a normal distribution, 10% of the cases should be below the 10th percentile and 10% should be above the 90th percentile. But in our series, we found that we had vastly more very small placentas and some of these placentas were 3, 4, 5 standard deviations below the mean in percentiles of 0.1, 0.01 or 0.001. These were extremely small.

How many excessive cases did we have below the expected frequency? Well, in our series, 47 cases were extremely small as represented by this area. There were also cases of stillbirths that had placentas that were significantly too large. Although the most common is a small placenta, there were certainly cases with placentas that were very large, probably again, because of being genetically abnormal.

Now, in addition to small placentas, we had other causes we found for stillbirth. The next most common was abnormal development or a genetic abnormality at about 30%. This is represented by abnormal infoldings of the cross sections of the fingers, the root system of the placenta, and the identification of something that’s called a trophoblast inclusion. These are labeled right here as TI, trophoblasts inclusion. That’s about 30% of the time we found that as the cause.

The next most common cause after that were cord accidents at almost 15%. Now, cord accidents are very unfortunate because they’re unexpected. Usually everything else is perfectly fine, except that a loop of the cord gets kinked. There might be a knot, the cord might wrap around the neck or some other body part of the fetus. These are very unpredictable and very sad and tragic of course.

The only thing good about a cord accident is that it usually doesn’t recur. The small placentas and the genetic causes that I just mentioned have a higher frequency of recurring. So it’s much more important to try to prevent those, if we can. Cord accidents, I tell most of the families that this is something that is of course a terrible tragedy, but it is not likely to occur again. It’s a chance event.

The next most common cause of stillbirth are infections at about 6%. Why are there infections in pregnancy in the first place? Well, there are always bacteria that live in the vagina and sometimes maybe there’s something wrong with the cervix in terms of how tightly it’s closed. Maybe the mucus plug has passed, or maybe there’s just bacteria in the vagina that are more virulent, stronger than usual. In whatever case, if these bacteria get through the cervix, break through the membrane, they start growing in the amniotic fluid. Unfortunately, the fetus then is exposed to this infection and it’s something like septic shock basically for the fetus.

The sad and difficult part about infections like this are that the space within the uterus is actually not inside of the mother. That doesn’t seem logical, but because there’s a continuous line, basically, you can take a catheter and go from outside of the woman’s body through the vagina, through the cervix, into the uterine cavity, infections that are inside of the amniotic fluid here do not trigger in the mother any reaction until the infection has been there for many days. For several days, at least, the fetus can be exposed to this infection and it can cause severe damage and even death. In our case, 6% of stillbirths were associated with these sorts of infections.

The next most common cause is abruption, which is the fancy name for saying a separation of the placenta from the uterus. This happened about 4% of the time. You can see different diagrams. Some abruptions or separations occur right at the edge of the placenta shown here, and although it’s dramatic because there’s blood that comes out and can come out of the woman’s body, it actually, luckily doesn’t cause a serious problem for the fetus because the placenta is mostly attached to the uterus. If this separation gets larger up to 50%, this can cause serious damage to a fetus. And if the placenta completely separates as shown here, that usually unfortunately leads to the death of the fetus or a stillbirth. That’s a serious cause, happens 4% of the time.

One of the rare causes, but again, so tragic because no one really knows that this is happening is what’s called a fetal bleed. Sometimes it’s called a maternal fetal hemorrhage. Basically, what it is is that the blood in the umbilical cord travels into the placenta, and at some point, there’s a rupture of the circulation so that blood can either leak out the side of the placenta. Blood can leak into the amniotic fluid or most commonly as exemplified by number three here, there’s a rupture of one of the vessels within the placenta, one of the fetal vessels in the placenta, and the fetal blood actually goes out into the maternal circulation.

There’s really no way to detect this unless you’re really looking for it. This is usually something that is unexpected. The only thing that the mother notices is that maybe there’s some decreased fetal movement and then there’s no fetal movement, and then a stillbirth is diagnosed. This is of course a very tragic case. Again, this does not recur very often. This is usually what we call a sporadic event.

Those are the different causes of stillbirth. What happened with MM? Let’s go back to my patient. Well, in this case, the placenta of her fetus, her baby’s placenta, remember the placenta belongs to the baby, not the mother, was less than the first percentile. You can see it plotted right here. It was very small. The reason it was small in this case is there is decreased maternal blood float to the placenta leading to increased fibrin, calcification of the fibrin, and actually death of parts of the placenta. That’s obviously an unfortunate outcome. In her case there was some elevation of blood pressure, but not enough to alert people that this was a problem, and of course they weren’t looking at the placenta, so they didn’t realize that it was small.

Why didn’t the OB know that the placenta was small? Well, it’s a complicated answer, but for the most part it’s because the focus of most of obstetrics and maternal fetal medicine is on the fetus. Why is that? Well, because everybody’s waiting for the baby. That’s what everybody’s paying attention to. But what I’d like to share with you is, not knowing the size of the placenta is like driving a car without a gas gauge. How does a car run just before it runs out of gas perfectly normally, and then it runs out of gas and the car stops. That’s what happens when the placenta is too small.

The question is, can we actually measure the size of the placenta? It turns out we can now do that. There’s a method called estimated placental volume that can look at a cross-section through ultrasound of the placenta represented by this red crescent here. I actually got the help of my father who was an engineer and a mathematician, and I said to my father, “Dad, if I give you the width measurement here of this cross section, the height and the thickness, can you create the equation to figure out the volume of this three-dimensional placenta?” He did that, and it turns out it’s actually easy to do and I’m going to show you an example of measuring an EPV on this ultrasound.

This is from a normal patient at 18 weeks, and here is the placenta right here in cross section, the amniotic fluid, and the fetus. If you take this picture and draw the width measurement from the tip to the tip, and then if you find the apex, which is right here, the top part of the placenta, and draw the line down to the base here, the width, make sure it’s 90 degrees, that’s the height. Then start at the same apex point, draw the line down through the same height line, but stop at the bottom of the placenta here. That’s the thickness. If you take those three numbers and stick it in the equation that my father created, you get the estimated placental volume. In this case, it’s 251 cubic centimeters.

Well, the first thing we needed to do is see if this equation actually worked. How did we do that? Well, with the help of one of my fellows at Yale, we looked at 29 patients between 29 weeks and almost 41 weeks and measure the estimated placental volume right before delivery, the placenta, the baby was delivered, the placenta was delivered. We clamped the cord and then weighed the placenta and we compared the actual weight to what we thought the weight was by estimated placental volume and found that there was a very good correlation. This is the paper that we published and I’m proud to say my father was a co-author on that.

Well, just proving that the equation works, it’s not really good enough clinically. The next thing we needed to do is actually create what are called normative curves. What’s the normal value at different gestational ages? The first study we did, we looked at 366 patients between 11 and almost 39 weeks. Here’s a plot of those patient results here. The red line on the top is the 90th percentile. The bottom is the 10th percentile and the green is the 50th percentile. We also did a study like this at Cornell, a different institution with completely different people and patients, 446 patients, developed the same normative curves. They looked actually quite similar.

Finally, a study that we just finished and haven’t published yet, I had one of my Yale medical students go to Senegal for a year. She collected an amazing amount, 1003 patients between 5 and 42 weeks, and these are her data points plotted. What’s interesting, if you superimpose all this data in one plot right here, you see that the data is almost identical in these three locations, whether it’s Yale, Cornell or Senegal.

Now, this is the master equation that explains the relationship between the estimated placental volume and gestational age. You can see that it’s a very good fit of this data. If you put that equation into an ultrasound machine, you can figure out the EPV with the ultrasound machine. This is actually Humberto Azpurua, who is my Yale MFM fellow, who was the first author of our first paper. This is a picture of him literally doing the first EPV ever done. This was done in 2008 and here’s the actual picture. In this case, we put the equation into the ultrasound machine and you can see it calculated the EPV for us.

Because the equation is not in all ultrasound machines, we decided that we would make a free app that people could use. Named it after my father Merwin’s calculator. Is very easy to use. It’s free in the Apple app store. You basically put in the measurements of the width, the height and the thickness, the patient’s name, the number of weeks and days pregnant she is, it calculates the volume and the percentile. If you flip the phone on the side, it makes the graph bigger. and it’s easy to see, for example, in this case at 19 weeks and 2 days that the placenta is in the second percentile. That would be quite concerning at that point.

Now, because people were asking us to also make an Android app, we were very lucky to have Michael Fredrick who works at Google and unfortunately was a loss dad himself. He was kind enough to make the same app Merwin’s calculator in the Android app store. Now you can get it on either app store.

In summary, when we looked at the different causes of stillbirth, we found that the number one cause was a small placenta. We now have a way to actually identify these cases and prevent stillbirths from happening. I want to point out that when we looked at just third trimester stillbirths– remember stillbirths are defined as 20 weeks to term. If we looked at the third trimester, which is the last 13 weeks of pregnancy, 36% of those cases were due to a small placenta. Now, only about 16 where the genetic and the next big cause actually after a small placenta were cord accidents.

Given that this is such a big chunk of the pie here, I think it’s very important for people to consider doing estimated placental volumes during pregnancy. One of the questions is when should this be done? I want to show you a cautionary story about one of my other patients of what happened to her. Unfortunately, she had a stillbirth literally right before her due date. No one knew why it happened, but I was asked to consult on this case and I determined that the cause, again, in this case, was due to a very small placenta.

Now, they had not done estimated placental volume ultrasound measurements in this case, but they had done a series of ultrasounds. I asked to look at them, and even though they weren’t planning on the EPV to be measured, I retrospectively went back and looked at them and calculated the EPVs. I plotted them in these blue pentagons right here.

You can see that at 20 weeks, it was basically normal. Then a few weeks later, it was a little above the 10th percentile. Basically between 20 weeks and let’s say 34, 35 and 40 weeks, the placenta barely grew. It really just stopped growing. However, her baby continued to grow. So he was almost at the 40th to 50th percentile while his placenta remained very small at term.

The ratio between his size, his weight and his placental weight was about 10 or 11 to 1. Normal is 6 to 1. A normal newborn baby should only be six times larger its placenta. He was over 10 times larger, which is why, unfortunately, he died. In my opinion, if the doctors taking care of this patient had known that the placenta actually stopped growing, they would have been more proactive in terms of delivering her before this stillbirth occurred.

Let me summarize what I think the messages here are that I’ve tried to share with you. Number one, it’s not your fault. It’s not your fault. It’s extremely rare that a mother can do anything. In fact, there’s almost nothing she can do to cause a pregnancy loss. All the causes that I’ve shared with you have nothing to do with what the mother has done, what she’s eaten, how she sat down, how she drove a car, how tight her shoes were, nothing. There’s nothing that she could have done to cause any of these losses. That’s the first really important take home message.

The second is it’s critical to diagnose the cause of the loss. Why did it happen? We can’t do anything about preventing something if we don’t know why something happened. It’s critical to get the diagnosis. In my opinion, the main place for getting the diagnosis is the placenta. If your local hospital doesn’t have the expertise to look at that placenta, make sure it goes to the pathology department and then find a consultant. Somebody who is an expert in the placenta to actually look at that placenta, to figure out why the loss occurred.

Once we know the reason for the loss, if possible, we’re going to try to prevent a recurrence. Now not everything can be prevented. Obviously, things like a fetal bleed really can’t be prevented because we have no control over the vasculature of the fetus within the placenta. However, immunologic rejection, clotting disorders, certainly a small placenta, the number one preventable cause of stillbirth can be prevented.

In the case of genetics, we can’t really prevent that, but at least we know in those cases that the highest frequency of recurrence risk is about 50%. Those families need to understand that, although they can have another loss, 50% of the time, they can have a completely successful pregnancy.

I’d like to end by acknowledging the people who helped me with some of the work that I presented here today. Beatrix Bebe Thompson graduated from Yale college last year. She has been a postgraduate fellow in our department and helping with the pregnancy loss paper and data I just showed you. Parker Holzer did the statistical analysis and produced these beautiful graphs that I showed you.

The Merwin’s calculator, obviously, my father was instrumental in figuring out the equations. My brother-in-law Matt Harper actually made the iPhone app. John Emerson helped with the statistical percentile calculations, and Michael Fredrick was nice enough to make the Android version of Merwin’s calculator.

You can find details of the papers that we’ve published. The ways to get us to help you look at any of your pregnancy losses and much more at our Yale website at klimanlabs.yale.edu. Thank you very much.

This presentation was part of the Stillbirth Summit 2021.   This individual lecture will be awarded .5 hours of continuing education credit to include viewing the lecture and completing evaluation and post-test.  Once received a certificate will be emailed to the address you provide in the post-test.  If you did not register for the Summit WITH Continuing Education, you can purchase the continuing education by clicking here.  This purchase will provide you access to all Stillbirth Summit 2021 lectures including continuing education credit. There is no charge for viewing the presentation.

To receive continuing education credit for this lecture, the participant must complete the evaluation and post-test.

Please feel free to ask questions of the presenter.  We will obtain their answers/comments and provide them here as received.  

12 Responses

  1. Angelica Kovach
    In Dr. Linda Ernst’s presentation regarding the value of pathologic examination in stillbirth, she said that it was of utmost importance to perform an autopsy. We did do a cytogenetic microarray when we lost our son (which came back normal), but were told by my physician that we weren’t likely to be able to glean anything else regarding a cause of death from an autopsy. You mention that the key to discovering the cause for stillbirth is in the placenta. For those of us who did not do an autopsy/feel remorse and guilt because of that, what is the likelihood that an answer can be found by assessing the placenta (or placental slides)?

    1. Dr. Kliman’s reply:
      Our studies have shown that a careful pathologic examination of the placenta can reveal the cause in over 99% of previously unexplained cases. Therefore, whenever there is no clear explanation for a pregnancy loss the placenta should always be examined. If you wish my laboratory to examine the placenta from your unfortunate stillbirth, please see this link for more information: Pregnancy Loss (https://medicine.yale.edu/obgyn/kliman/placenta/pregnancyloss/ )

  2. Annie Kearns
    You mentioned genetic anomalies as a cause of small placenta but also as its own cause of stillbirth. Are these overlapping? Or does the former refer to only cases of mosaicism?

    1. Dr. Kliman’s Reply:
      Losses can occur due to a small placenta by itself. The major reason for a small placenta is a genetic abnormality. Losses can also occur due to a genetic abnormality, independent of the size of the placenta.

  3. Angelica Kovach
    How often do you see stillbirth from a small placenta/placental insufficiency in babies lost early in the third trimester (in my case, 33 weeks and 5 days gestation)?

    1. Dr. Kliman’s Reply:
      In our studies we showed that 36% of third trimester stillbirths are due to a small placenta. Additional information about trying to prevent another loss due to a small placenta can be found here: Estimated Placental Volume (https://medicine.yale.edu/obgyn/kliman/placenta/epv/)

      This link also includes a number of articles related to EPV.

  4. Linda Ernst
    Harvey- thanks for your talk. Why have OB’s not adopted this technique for estimating placental volume? It would be so informative! and is so important as a risk factor for SB and many other problems

    1. Dr. Kliman’s Reply:
      Great question! Many Obs and MFMs do not wish to do something that has not been endorsed by their official professional organization (ACOG and SMFM). In the meantime, we continue to collect data to validate the utility of EPV. We also try to help individual patients who have had a previous loss due to a small placenta find a doctor who will do EPV measurements during their subsequent pregnancy. See this site for much more information on EPV: https://www.measuretheplacenta.org

    1. Dr. Kliman’s Reply:
      It depends on the cause of the small placenta. If the cause is genetic, this cannot be prevented. If immunologic rejection, then we can treat the mother to decrease the problem.

      Whatever the cause, the key is to measure the placental volume and use that information as PART of the decision making process to determine when to delivery the baby.

  5. Whitney.Thoma
    A patient finds out her placenta is small, What does the doctor do to ensure a healthy delivery?

    1. Dr. Kliman’s Reply:
      The key is to measure the placental volume and use that information as PART of the decision making process to determine when to delivery the baby.

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