Maternal-Fetal Surgery: The Clinical Promise and the Ethical Pitfalls

Elena Gates

Thank you. It's actually a real privilege to come at the end of such a wonderful day of talks, and thanks to our organizers for inviting me and putting this together. It's going to be challenging to incorporate a lot of great ideas that we've heard into what I'm going to say. I'll warn you ahead of time that I did change the order of slides a little bit, so hopefully you won't be too impatient with me. I'm going to start with a picture just to sort of let this sink in while I'm talking of what part of this enterprise of maternal fetal surgery is all about. This is the mom. This is her uterus. This is the fetus with an arm and a thorax, the head's up here. And this is a lung mass that they're removing from this fetus who was in danger of dying from hydrops because of the burden of this large lung mass. I grew up as an obstetrician at UCSF at the same time that our fetal treatment program was developing there and have been really involved with it pretty intimately over the last, I'll doubt myself, 20 plus years.

Elena Gates

Mostly as a member of the Ethics Oversight Committee for the program and also as an obstetrician caring for patients. It's been a really long journey, lots of missteps, two steps forward and one step back. I think the main thing that I want to acknowledge to you up front and that I'll allude to as we go along is that even though we're 25 years into this, there still aren't many data that support the effectiveness of the interventions that you're going to be hearing about this morning. And we need to really keep that in mind, particularly when we think about how we discuss them with patients. Because you can't be compelling someone to choose an intervention that might put her at risk if we really have no data to support the fact that it's effective. So evidence is one of the many, many gray zones. And thanks for that terminology, John. This is helpful. That we're going to be having to confront when we think about maternal fetal surgery. It's been 10 years. Wrong button.

Elena Gates

to the month since a NIH-sponsored conference on scientific, ethical, and clinical considerations in maternal fetal surgery that I attended, along with some others. And part of the discussion there was to enumerate some of the ethical concerns. Four of us put together a report. Our lead author was Annie Lyerly, who still is very active in ethics as an obstetrician. And I think it will be interesting for us to look back and see where we've come in terms of these. One of the big concerns early on was maternal outcomes. People were really focused on these surgical interventions on fetuses and not paying a lot of attention to understanding the impact of these surgeries on women.

Elena Gates

There was a very serious trade-off between the potential to help these children avoid disability and increasing their health concerns because of the almost universal fact that these babies are born prematurely after these fetal interventions. Early on, the focus was almost primarily on trying to save fetuses who had a lethal condition like hydrops. It's going to kill them if you don't fix this, for example, with the surgery I showed you within a few days. and thinking that it really wasn't appropriate to apply these procedures, risky procedures, to anything but lethal conditions. And I think that's one area where thinking really has evolved for many of us. And we now wonder whether saving the life of a fetus who would otherwise die and resulting in a child who's living with serious disability in the case of, for example, a really severe congenital diaphragmatic hernia. You guys know how those children have lots of health conditions going on. Is that beneficial to that child? Is death less burdensome than a life with disabilities? I'm not going to answer that. Oh, my thing's not working. OK, sorry. But it really makes one wonder whether the focus on lethal conditions is really the appropriate one or should we be selecting fetuses who have a condition that we could actually correct and lead them to live a life that is less encumbered by disability than it would ordinarily be and I'm beginning to think that that is maybe the better goal if we can actually figure out how to accomplish it from a technical perspective. There is a lot of potential impact on the ability of women to make choices about where they're going in pregnancy when they're faced with a fetal anomaly, and then looking to the future, a lot of concern about entrepreneurism and how these techniques are disseminated and fetal medicine practices growing across the country. So I'm going to touch on where we are with each of these. First of all, a little bit about the evolution of the surgical approach. The fact that serious harm to the pregnant woman would have been a showstopper for the enterprise had it ever happened. Had we had maternal deaths, you know, year after year in these centers, we wouldn't be where we were now. There was a lot of incentive to try to decrease risk to women. And this actually was successful largely because of a gradual trend towards doing less and less invasive procedures. So nowadays, most of what we do, I'm not saying we, I'm not a fetal surgeon, but in the enterprise is done through two or three millimeter

Elena Gates

tools, scopes or lasers that go through the maternal abdomen to either cut amniotic bands, to put a balloon in the trachea in the case of severe congenital diaphragmatic hernia, laser ablation for twin-twin transfusion syndrome, radiofrequency ablation for sacrococcygeal teratomas, for example, or balloon valvuloplasties to try to prevent left ventricular hypoplasia.

Elena Gates

So from that, we've moved to this, where you can imagine a woman doesn't even have an incision in the skin anymore, doesn't end up in the intensive care unit, doesn't always need general anesthesia, can get out of the hospital, can have a vaginal birth at the end of the pregnancy. And little by little, preterm birth has decreased as well as these techniques have improved. The main complication still is preterm premature rupture of the membranes. In one of the few randomized trials looking at any of these interventions, a randomized trial of putting the balloon into the trachea in fetuses with congenital diaphragmatic hernia to try to get fluid to accumulate and the lungs to grow, the majority of the babies in the intervention group had PPROM and preterm delivery. And, of course, in the conventional expected management group, this wasn't the case.

Elena Gates

risks have dropped and again I mentioned this as sort of the showstopper that people had feared the bar for letting this trickle out more broadly into more and more hospitals around the country is lowered and I don't know if this is a threat or an opportunity and we'll talk about that a little bit as I go on. I also want to mention before we leave the risks to women This is actually a risk to family. I think we're only now beginning to understand the magnitude of what we are leaving these families with. Again, these are families who, at least given the past interventions, would have had a fetus that died or an infant that died shortly after birth. And now they have a child who's 3 or 5 or 10 or 12 years old who's living with chronic illness or disability. Is that a benefit to them? No one's really following up from the psychosocial perspective, largely because it's hard to get anybody to pay for those studies. But those data will be really valuable once we, or if we ever obtain them.

Elena Gates

We've had a lot of great discussion about maternal and parental decision-making about fetal and newborn well-being this morning, so I don't need to sort of go over with you the dynamics of that and the importance of helping our patients to understand how they value the possible outcomes that nature has handed them. But I do want to just reiterate the fact that when women come or families come after a pregnancy has been diagnosed with a fetal anomaly, we see a wide diversity of goals Some want to avoid anything that's not absolutely normal, and those people often choose to terminate the pregnancy without really hearing much more about further options. Others feel that they want to try anything that might possibly benefit their future child. Many just want to meet the child, see it born alive, and if it dies, that's what's going to happen, but their goal is to meet their baby. And all of these really challenge our typical obstetric thinking, which in the past has been pretty linear. You do whatever you can do to maximize healthy mother and healthy baby. And now we have all of these options that are being offered to people that are pretty innovative,

Elena Gates

sometimes explicitly experimental, and can sort of have us wandering down this path of very complicated choices trying to get to the goal that the woman and her partner have chosen. People may choose to terminate the pregnancy. They may choose intervention during pregnancy. These last two we've talked about already this morning, aggressive intervention at birth, comfort care at birth. And I think where it gets really interesting is where people can combine these choices, if this, then that, and you get into this complicated decision tree depending on the outcome at any particular spot. In terms of maternal choice, one of the concerns that we had 10 years ago was that if we ever got to the point where some of these interventions were actually shown to be effective, would women feel less able to choose to terminate a pregnancy. For example, if we knew that you could pretty effectively manage congenital diaphragmatic hernia with a prenatal intervention, would it be irresponsible, to sort of bounce off Mark's comment, irresponsible for a woman who had desired a child to choose, she didn't want to go down that path and to either have an abortion or perhaps even worse, to withhold that treatment from her fetus and say, you know, I can't take those two months off work. I have three other kids at home. I just can't embark down this surgical thing at this point. I'm just going to wait and have a baby. What we often see as well

Elena Gates

is a situation where the woman starts down one path, doesn't work the way she wanted, and then she changes. So trying laser for twin-twin transfusion syndrome and finding that, in fact, both fetuses do have brain injury on MRI and choosing to terminate at that point. Or trying a fetal intervention, seeing as the pregnancy progresses that the outcome still looks pretty bleak and deciding to have comfort care after birth rather than aggressive neonatal management. Sometimes these seem like real inconsistencies to us as obstetricians. I think the one is that's the hardest is the last one, to have a woman whose fetus has a

Elena Gates

defect or condition that we know is incompatible with survival, severe congenital diaphragmatic hernia, Potter's syndrome, for example, and to have her say, my main goal is to meet my baby before it dies. I don't want it to die during labor. I want a C-section. And then we'll provide comfort care for my baby and that my baby and my family and I can sit together for a while before it dies. And this is really different than what we typically do in obstetrics and people push back against that a little bit. I included some cases in the slides that I don't have time to actually go through with you, but one of them is a story of a patient with a fetus with hydrocephalus where that was the choice that she ultimately made. So what we're working through with our patients are a lot of trade-offs, maternal risks versus benefits to them to have a healthy child, benefits to their children, perhaps incremental harm to infants from the intervention, largely because of prematurity. Do we value differently iatrogenic disability, something that we caused versus something that nature brought to us? We heard about dealing with the deck of cards that you're handed.

Elena Gates

Is it worse for a child to have one severe disability or a bunch of smaller ones, particularly if the latter were perhaps things that we brought about because of our interventions? And for many families, the ultimate question is, is it worse to have a child with a serious disability than no child at all from a particular pregnancy?

Elena Gates

I want to pause here just to Sort of think back to what we heard earlier this afternoon about

Elena Gates

reproductive choice and decision making in the setting of childbirth. As obstetricians, our culture is very much focused on the woman as the decision maker in relationship with her family, her partner, her other children, also in relationship with her fetus, but she really is the focus of our decision making. And I think it has worked very well in the group that we have at UCSF who counsel these women when they come through for evaluation and to consider their options. It's a multidisciplinary group with maternal fetal medicine, fetal surgery, neonatology, social work, and nursing. As I was sort of updating myself on what's going on around the country, I was quite intrigued to see that there now are fetal pediatricians I don't know if you have any at the University of Washington or not, but I think that's quite an interesting term. John Lantos is smiling at me because he knows that I'm going to talk about a paper that he's a co-author on that I would recommend to all of you who are working in the children's hospital world. And it really talks about pediatric-centered fetal care, which is a huge frameshift from this obstetric-focused care for the pregnant woman. Because here you have people whose culture is to focus on the well-being of the child and extending the concept of the child all the way back to where it's a fetus, the fetal pediatrician. The priorities are going to be different than they are in prenatal care. The obligation of the provider is going to be to the fetus. It's going to be on protecting the child, which protecting against what? Protecting against the mother? Well, it's inside the mother. So it's not entirely logical to remove it from her. I

Elena Gates

wonder really how the counseling about some of these interventions may change if it's a fetal pediatrician who's doing the counseling as opposed to an obstetrician or maternal fetal medicine specialist in terms of framing the obligations that the woman may have to her fetus. And it's particularly important here to keep in mind the fact that we still lack the evidence to show that most of these interventions are effective. So we have to be really careful about how much we try to sell them to people. This is a fun little slide where I collected some of the logos of these fetal treatment centers, many of which are in children's hospitals around the country. We've sort of lost the mother, and I think we've lost the pregnancy. The pediatric surgeons at UCSF have, over the years, expressed a lot of frustration. If it weren't for that damn preterm labor, it would be fine. Or if it weren't inside that uterus, this would be really easy to treat. Also, they just get rid of it here.

Elena Gates

Here, you can see the breast and the abdomen in this one, which is sort of nice. These, they're actually providers' hands around this little, this is like a 12-weeker here, and the hand of the surgeon. This is the one Mike Harrison came up with years ago at UCSF. This is our new logo. Here's the NAFNet, which I'll talk about in a minute, and you have actually an instrument, it looks like, that's in this picture. Maybe this is a mom. This looks sort of like the Seattle Children's Hospital one, I think, a little bit. So maybe that's the mother. But it sort of looks like a sperm, too.

Elena Gates

I don't know. That was to wake you back up again before we get back to the business. The CDH story, I don't see it in my clock. But I think I may need to talk about this. Am I good? OK. The CDH story, I think, is sort of a paradigm of how we have tried over twenty years to accumulate evidence to do good clinical trials over and over they keep failing to show us benefit uh... from open repair to using uh... open clip on the trachea to the balloon thing i showed you the picture of earlier uh... stricter and stricter inclusion criteria all along the way neonatal care improving at the same time so your comparison groups keep And at the end of the day, it's really been hard to show that we've made a positive impact on the health of children, even though all the enthusiasm has been maintained. It leads me to question whether we're really practicing evidence-based medicine, which is a mantra for many of us these days, or continue to be sort of hope-based. Well, it's got to work if we just can figure out how to do it right. If we can figure out the right study design, we can show you that this is working. I'm not optimistic that this is ever going to happen.

Elena Gates

One of the effects of this, though, is that the public and patients who have fetuses diagnosed with anomalies are convinced that this must be treatment, because we're using that word. The centers around the country call them fetal treatment centers, fetal treatment programs. People magazine gets this on the cover. and people are convinced that they need to try this if they have a fetus with one of the conditions for which attempts at intervention are being made. Some of you may have heard of this, the MOMS trial, which was actually conceived of at the same NIH conference that I mentioned earlier. It's now almost completely enrolled, 200 pregnant women and their fetuses were up to about 177 or something like that. The DSMB is meeting more and more frequently, so I think we're figuring that soon we will actually have some information from this trial. It may show benefit. It may show some equivocal results. It may be the most likely outcome. I don't think it's likely that it's going to show substantial harm, or we would have heard something before we had accrued quite so many

Elena Gates

individual patients. This has been done at CHOP, the Children's Hospital of Pennsylvania, and at UCSF. Vanderbilt was also part of it, but through some logistical misadventures, dropped out as a center. There are centers all over the country that are now gearing up to be ready to offer this procedure as soon as the findings from this trial are publicized. And I'd like to think with you sort of as we wind up here how we're going to handle that and what the implications of that might be. Here's another photo just to sort of point out to you the magnitude of this enterprise. a complex procedure, a risky procedure. Again, it involves laparotomy, hysterotomy. This is the uterus. This is the fetal back. This is a little patch that our pediatric neurosurgeon put across this fetal back. Sometimes they are able to do a primary repair. You can see this is two centimeters in diameter. Most of us who do basic obstetric surgery or GYN surgery or anything else wouldn't be capable of this. It also has been accomplished in two centers that have had

Elena Gates

very mature fetal treatment programs for a long time with a really integrated multidisciplinary team and very clear clinical pathways that really watch for all sorts of harms that might come and where we have counseling processes that are really robust and multidisciplinary. So as we move forward, I think we're going to be facing a lot of enthusiasm and a lot of entrepreneurism on the part of centers around the country and surgeons and obstetricians who really want to be offering this to their patients. Someone mentioned earlier that the NICU is such a lucrative source of a lot of income for children's hospitals, and I think that's part of what's gotten hospitals behind these centers.

Elena Gates

The North American Fetal Therapy Network is a group that has come together to foster collaborative research in fetal medicine, and I think a group like this might be quite effective in agreeing on how to move from a study to actually clinical application of a new intervention. in terms of agreeing on the criteria for inclusion. In a study, if a woman comes and says, I'm interested in the study, and she's not eligible based on your inclusion exclusion criteria, you can say, I'm sorry, you're not eligible. If you have a woman who has a fetus with a myelomeningozele who says, oh, come on, please, this is my only hope. You've got to let me in. You've got to try this. It's going to be much harder to be strict in terms of application of the procedure to the right fetuses. I think a network like this could help with quality reporting and perhaps most importantly to continue to generate the outcomes, the data that we need to know moving forward whether this really is the right thing to be doing. So that's all well and good, but I'm not sure it's going to be the way that things will roll out. I'm going to show you a couple of examples of materials that are already up on the internet promoting fetal treatment around the country.

Elena Gates

This one, I don't think anybody in the room can read this, and that's part of the point, the magnitude of what they're offering. But the top of this says, these are conditions treated and fetal therapy options, implying that these are all things we can fix in your fetus today, right? Is that sort of how you read this? So pulmonary agenesis, omphalocele, encephalocele, I'm not aware that any of these things are being treated in utero. Again, the one where we seem to have pretty good consensus on effectiveness is laser treatment for some pregnancies with twin-twin transfusion syndrome, but there are a lot of other things up on this list that really can lead to misconception on the part of the public. And this, another center in Denver, some of the fetal conditions we diagnose and treat. It's a pretty unequivocal statement. And then if you look down the list, I see hydrocephalus. Treatment for that was tried with shunts back in the 80s and early 90s and was pretty much agreed upon as an area where this wasn't going to be helpful. Some of these, there are some very early experimentation, valvuloplasty for congenital heart disease, but I think this is pretty...

Elena Gates

misleading to a woman who's searching the web because she just found out that her fetus has, for example, an emphyseal. So I'm going to end with the pitfalls of marketing and rapid dissemination. I think we continue to struggle, even among physicians, obstetricians around the country and pediatricians, with confusion about what's an experimental intervention, what's a proven therapy. And we'll continue to do so, probably because we're never going to have all the data that we need to really know what we're accomplishing. Informed consent is really complicated, and I fear that the process may not be optimal. I'll show a little bit of my own bias as an obstetrician in terms of my concern about fetal pediatricians counseling pregnant women about their options.

Elena Gates

I'll take questions about that during the panel if anyone wants to push back. The learning curve has been a really, really long slog for people who have been doing this surgery for a long time. And I think the failure to collect data and perhaps divert patients from future trials is another thing that we need to be thinking about. I also want to circle back one last time to that gray zone, and I guess I'll I'll hope that at least as far as the women and families who are making decisions about the use of these interventions, we continue to be in a gray zone and nobody starts to think it's black and white and these are effective and you must do this if your fetus is affected with, say, a myelomeningocele or a congenital diaphragmatic hernia. So there I'm going to welcome the gray zone for a long time. And thank you very much.