Okay, let's get started with the webinar. Welcome again to today's AOAAM webinar on Treating Opioid Use Disorder in Pregnancy and the Perinatal Period by Dr. Davida Schiff. My name is Julie Kmic and I'll be your moderator for this session. This is the last of our six-hour webinar series on hot topics in the treatment of opioid use disorder. I'd like to introduce Dr. Schiff, who is a general academic pediatrician and health services researcher focused on understanding how substance use in pregnant and parenting women impacts the health of children and families. She is the medical director of HOPE Clinic Harnessing Support for Opioid and Substance Use Disorder in Pregnancy and Early Childhood at Massachusetts General Hospital. Dr. Schiff's research is focused on improving care for families affected by substance use. She's an assistant professor of pediatrics at Harvard Medical School, so I'd like to welcome Dr. Schiff. Thank you so much. Can you hear me okay? Okay, perfect. Hi, everybody. To those of you who joined last week, welcome back. For those of you who are joining just for the case discussion, so glad to have you. I really am using the time today to respond directly to questions and comments that came up in the first session, so I hope that you guys will find this to be valuable. And please type in questions throughout. I'm happy to stop and answer them at any time, or similarly to how we did last time, we'll leave a good 15 minutes or so at the end for questions. So I have no financial conflicts of interest that I want to disclose today. I have received research and programmatic funding from the following institutions, as well as some funding for consultant work from the AAP. My objectives for today's talk are to discuss buprenorphine microdosing protocols and their use in pregnancy, to review methadone metabolism and how changes in physiology during pregnancy impacts the metabolic process and methadone metabolism, to understand the benefits of split dosing in pregnancy, and understand the sort of benefits and risks to split dosing in pregnancy. Sorry, one second. Okay. And then to review the maternal-fetal risks of medically-assisted withdrawal during pregnancy. Then finally, there's a few lingering questions from last week that I couldn't kind of fit into those cases, and so I'll answer them at the end. So let's get started. The first piece that I want to discuss with everybody is a 24-year-old who is presenting at 24 weeks, and she's been using fentanyl daily. So she's a G2P1, and her pregnancy has been complicated by significant nausea and inability to tolerate her sublingual buprenorphine really throughout her first trimester, and has contributed to a recurrence of her daily opioid use. Her medical history during this pregnancy is notable for a diagnosis of COVID at 18 weeks, which she's now recovered, although she has had some lingering respiratory symptoms. Her substance use history is notable for a six-year history of opioid and stimulant use disorders. She has a remote history of alcohol use disorder, but no alcohol use this pregnancy. And really, prior to her pregnancy, she had stabilized for the past six months on sublocaine, but had transitioned to buprenorphine sublingual when her pregnancy was identified at six weeks, just six weeks gestation. Her psychiatric history is notable for a diagnosis of bipolar disorder, PTSD, anxiety with panic, but notably she stopped all of her medications when she learned of her pregnancy. Her social history is notable for being recently separated from the father of the baby, had been a stabilizing force for her recovery, and that she continues to work at a daycare several times a week. You guys make a plan for admission to your hospital for inpatient stabilization and buprenorphine microdosing. So I wanted to just briefly review what buprenorphine microdosing is before we get to what the specifics could be in pregnancy. So as a reminder, the classical induction approach, which I imagine is not new to any of you, involves asking patients to abstain from all full opioid agonists and wait for mild to moderate withdrawal symptoms prior to having them take their first dose of buprenorphine. You typically start in two to four milligram increments and go up and sort of titrate to effect. But yeah, with the rise of fentanyl and really other long-acting opioids, there's been an increase in precipitated withdrawal using this traditional or classical approach, which is felt to be partly related to the increased lipophilicity of fentanyl, which can lead to a higher volume of distribution, a prolonged clearance with consistent use. And one of the worries is that complicated or failed inductions can be associated with poor long-term treatment retention and an increased risk of relapse. So because buprenorphine has a high binding affinity of the mu receptor, but a low dissociation constant, and the idea is that low and incremental doses can be administered alongside or concurrently while a person is still either using a full opioid agonist such as fentanyl or heroin or in a transition from methadone through buprenorphine. So this idea, microdosing or the Bernese method, is to slowly over time, using 0.25 to 0.5 milligram doses of buprenorphine, you gradually will have the buprenorphine replace the full agonist, the mu receptor, without precipitating any withdrawal. There is a recent review that was published in the American Journal on Addictions that I think does a really nice job at sort of summarizing what we know in the published literature around the sort of success of using buprenorphine microinduction by this group in Boston. And what they found were there were 18 papers who met their sort of inclusion criteria of successfully treating a patient using micro induction protocol. So the experiences of 63 patients were described, and there's really a range of approaches. So the initial doses ranged from 0.2 to 0.5 milligrams of buprenorphine. Both transdermal buprenorphine patch and bupa cell have been used, and the protocols in terms of how long you continue on the microdose before increasing your dose and before you stop the full agonist also varied quite a bit. So the protocols ranged from 7 to 10 days until full opioid agonist is stopped. The range was actually quite long, ranging from 3 to over 3, 3 days to over 3 months. And ultimately people were initiated on average of buprenorphine doses between 8 and 16 milligrams. They noted successful inductions with individuals using a range of full opioid agonists, including heroin, oxycodone, methadone, hydromorphone, diacetylmorphine. But really, I think the review highlighted that there's no consensus on a singular microdosing approach. So what does that mean in pregnancy? This came up a couple times in the question and answer session. And to date, there's no published reports of microdosing protocols in pregnancy. Many centers around the country are using different protocols, and I wanted to just provide two of them that have been shared with me. This comes from Mishka Turklin and colleagues. They put together a fully outpatient protocol where, as you can see, they start off for the first two days with 0.25 milligrams. They go up to make it twice a day, increase to 0.5 milligrams. By day five, they're up to 2 milligrams VID. And then on day seven, you titrate the symptoms and have fully stopped your opioid agonist right before day seven. This is another protocol that's from Larry Lehman's group at the University of New Mexico FOCUS group that I mentioned last week. And they have a slightly longer, slightly more sort of stepwise approach where you start off with 0.5 milligrams daily for two days. Then you go to do 0.5 milligrams twice a day. You'll eventually go up and do a milligram twice a day. And as you can see here, they don't have you stop until day 11. And then you sort of titrate up to the effect. Although they do note that if you feel like you can stop prior to that, then it's okay to do so and to follow up with your doctor. This is another, this is actually a patient-focused guideline that was shared by Tricia Wright on a women's addiction group, LISRV, that if any of you continue to be interested in this topic, the ECM runs a women's addiction group, LISRV, that I think has been a really valuable place for me to learn about these different protocols. And really, this approach says the same thing. Here, they stop on day seven. So I think the variety, when you sort of start to take a look at the different protocols, and what I would kind of leave you guys with, as you consider what microdosing in pregnancy looks like, is there's a few things for you to kind of weigh. One, should this be done as an inpatient versus an outpatient? Two of those protocols were ones that were done very much exclusively in the outpatient setting. I think what we know is that practice varies and there has been successful home induction for centers that can facilitate antepartum admissions, or even admissions to medicine. I think you can improve the chance of successful induction. You can reduce the chaos of the drug use environment, offer respite, monitor, and comfort medications. Sort of the initial Bernese method, as it was described, was initiated in individuals who were in the inpatient setting. I think there's certainly been more success among individuals in the inpatient setting, but I think many people have tried home inductions in pregnancy and it's felt to be safe. Particularly when it's in the pre-viability stage. Similar to the general population, I don't think there's no specific protocol. There's no clear standard. And I think, this will hopefully be a theme in some of the other cases that I present today, patients' prior experiences can help guide you. And I do think that they are the experts in their bodies and what they know and what they need. And often their experiences, using these medications in a non-prescribed way can sometimes guide their experiences and working towards transitioning off of full opioids. Okay. I was just wondering, we had a question. In your review of the articles, was there anybody that was using street fentanyl? Yeah. So the review doesn't specifically highlight fentanyl. In the 18 articles that have been published about this to date, in the sort of reason for why the micro-dosing protocols have been developed, I think there's been a huge understanding that it's harder to use the classic induction for individuals who are using high amounts of fentanyl. And that this approach has been sort of developed and kind of really refined because of the high contamination of fentanyl in the drug supply. Thank you. Yeah. All right. I'll move on to case two, which is a methadone case. So this is a 33-year-old. She's a G10 P2 at 13 weeks gestation. She has a complicated psychiatric history with a diagnosis of major depression with multiple suicide attempts. But some question about whether she has a bipolar mood disorder that has never been fully diagnosed and severe anxiety and PTSD. Her substance use disorder history is notable for severe opioid use disorder. She actually has been prescribed 24 milligrams of buprenorphine, but really has had ongoing cravings and use. And prior to her pregnancy, really has been treatment naive with more than a decade of injection drug use. Her social history is notable for not parenting her older children at the moment. And she currently has just managed to get herself into a family residential treatment program and is really motivated to engage in treatment right now. So she was admitted for antepartum stabilization on methadone. So what makes methadone induction in pregnant people different than non-pregnant people? There really are just a lot of physiological changes that happen during pregnancy. So your body fat increases, which increases your lipophilic storage. We just reviewed that full opioids, specifically fentanyl, have sort of high lipophilicity and can get stored in that excess fat tissue. Your blood volume increases, so you can have dilutional effects. There's increased drug clearance. So we know that 3A4 from the liver, placenta, and intestines kind of get activated. So you have changes in drug metabolism and also enzyme genetic diversity that can come out. Your gastrointestinal motility slows, so it can affect oral absorption. You can have changes in protein binding. And then probably really an important notable one that makes considerations around medication use in pregnancy different is that there's parental consideration of fetal risks and harms with concern for risk of neonatal opioid withdrawal. So how do you think about methadone dosing in pregnancy? We expect there to be increased methadone requirements because of the physiologic changes that we just went through. There's kind of a well-established literature that shows that higher dose is correlated with less non-prescribed use and vice versa. So a lower dose is correlated with greater increased non-prescribed use. And we have clear literature that supports that an artificial cap on dose is not advised. So 15 years ago, there was the sense that we shouldn't be using more than 60 milligrams of methadone in women and that they shouldn't breastfeed when they're on doses higher than that. And that is just clearly not advised or recommended or good practice at this point. I think there's emerging evidence for serum testing, which we'll talk about in a little bit more in detail in the next case. I think overwhelmingly the current practice is regular symptom follow-up for dose adjustments, but there are some ways to use serum levels to guide you. It shouldn't predict dosing needs between patients, but it may guide treatment over time in a patient. So you can measure the serum methadone level and compare peaks and troughs at a steady state. But what I'd like to describe in a little bit more detail in the next case is something called the methadone metabolite ratio that Dr. McCarthy and his group kind of have helped sort of study during pregnancy to assess for metabolic changes, where the lower the number, the more rapid the metabolism. I wanted to also talk about some induction challenges that are unique to pregnancy. So pregnancy and opioid withdrawal symptoms can often overlap. So feelings of nausea and vomiting that are so common to all pregnant people really can often be someone's primary kind of presenting opioid withdrawal symptoms. It's difficult at times to tease out the timing. So symptoms at peak dose, non-overlapping symptoms, and then co-occurring psychiatric illness can also make it difficult. There's really limited to no literature on what is the recommended in-hospital titration rate for pregnant women. So it's a real need to balance risks of over-sedation, knowing that those first four to five days, even if you don't do a dose increase, you haven't reached steady state. With kind of the half-life, with patient tolerance of the induction, with the desire to have patients not feel symptoms of withdrawal and cravings. There's also fetal considerations. So the safety of comfort medications in pregnancy. I think in our institution, Clonidine, Benadryl, and Zofran are felt to be kind of the first line and real aim for judicious use of benzodiazepines, mostly because of the known kind of potential risks to the fetus. In our institution, there's kind of routine ob-fetal monitoring that happens on admission. The goal is to do it not at the peak dose and then growth ultrasounds for anyone who's greater than 28 weeks. So let's talk about a different case and then think through some of the challenges with methadone. This is a 33-year-old, G9P4, who is at 30 weeks. She's also had daily use and is currently on 200 milligrams of methadone. So this is a patient who's had severe opioid use disorder since 15. Her medical history has been complicated by endocarditis, hepatitis C, multiple non-fatal overdoses. She actually has managed to put together five years of abstinence on methadone in the past, and has had a history of stimulant use disorder with cocaine, but currently is not using it regularly and does have tobacco dependence. Her psychiatric history is notable for anxiety with benzodiazepine dependence. She has a history of attention deficit disorder and postpartum depression in her prior pregnancies, and has been out of care and taking non-prescribed clonazepam for at least the last three months. Her social history is notable for parenting her three oldest children until about three years ago, and then had a heavy recurrence of use when there was a removal of her children to child welfare. There was an open adoption with kind of quarterly visits each year, and that she has an 11-month-old who's her youngest who's been adopted, and that was a pregnancy that was complicated by active drug use throughout. So initially, this was a patient who was managed in our outpatient clinic, so she actually had weekly visits between 17 and 20 weeks of her pregnancy, and then was sort of difficult to connect with. She had outreach phone calls with her peer and connected then, but wasn't able to make it in, and despite then being on 150 milligrams of methadone maintenance had ongoing withdrawal cravings and use several times a week. At that point, she was living in a neighborhood outside of Boston with her partner, complicated relationship, and she had very clearly stated her goal was to get into residential treatment so that she could keep her baby. Her medications when she was admitted to the hospital are listed below. So when she came into us at 30 weeks for her methadone titration, we were able to confirm that her dose had been increased to 200 milligrams at her outpatient treatment program, and that she endorsed using daily heroin to avoid being sick. She does report in her prior pregnancies that she'd required at least 300 milligrams and split dosing, and she was requesting the increase of all of her psychiatric medications in addition to residential treatment placing. Her admission tox was positive for multiple substances, including methadone that she was receiving at her OTP, and her EKG and admission had a normal QTC. So I wanted to raise just a few issues. The first is how do we ensure a safe hospitalization and stabilization? Is split dosing reasonable or realistic or feasible for this patient? And how does methadone dose affect the fetus? This patient was actually really clear about what she needed. She's like, I know what dose I need in my pregnancy. I need 300 milligrams. During her hospitalization, she had ongoing cravings, sweats, hot, cold, flashes, lack of appetite, irritability, restlessness, clear signs of opioid withdrawal. And yet also had kind of a challenging hospital course where she spent an extended time off the floor. There was no documented sedation, no increase in her clonazepam. And so this was the kind of course over prolonged hospitalization where she went from about 200 milligrams of methadone on day one up to 300 milligrams on day 20. Her QTCs remained in the appropriate range. I just wanted to highlight for you guys some of the challenges of this patient's prolonged hospitalization to see if there's similar things to what you're experiencing in your care. One, this patient had an incredibly high opioid requirement which was due likely to her high dose methadone with concurrent IV fentanyl use, her baseline metabolism, and her pregnancy physiology. But she also had this very fixed perception on what her dosing requirement was. I think the next kind of issue that came up was really what was the appropriate level of care for her and what was the realistic end of hospitalization? I think everyone really wanted to get her feeling stable and get her to a residential treatment program. But when med stabilization and program linkage is the only active hospital issue, we've noted that it really causes conflict and there can often be sort of issues that arise within the inpatient setting where a healthy hospitalized patient who's taking extended time off the floor causes real communication challenges between teams. So frustrating disposition issues and then specifically thinking about practical challenges in terms of whether this patient could be started on split dosing if there was no way to discharge them to a methadone clinic that would allow that split dosing to continue. So a quick detour on behavioral issues on the antepartum floor, because this is something that really early on while we were doing this work caused a lot of challenges for individuals who were leaving the floor for long periods. There was the sense that perhaps they shouldn't be admitted to the hospital at all. There were patients who butted heads with the smoking policy and visitor policy in the sense that in a lot of ways they were too healthy to be in the hospital. So how did we work to improve patient experience and care team experience? I think I mentioned this last week, but I can't underestimate how important it is to have peer support. So to have peers be able to support patients while they're in the hospital setting, their allies have walk with them for supervised walk breaks or smoke breaks that really can make a difference. And then we created a guide for patient engagement and expectations. And that was done in collaboration with our inpatient colleagues to sort of address what this hospital stay is gonna be, what the expectations are for both the patients and the care team. Okay, so to get back to the clinical case, now this is a patient who would clinically appear overmedicated several hours after dosing, but experienced withdrawal before the time for the next dose. So what's happening in terms of her methadone pharmacokinetics? I wanted to describe this ultra rapid metabolism pilot study that was done where they followed 23 women with serum methadone to metabolite ratios. And they looked at the number of individuals who are rapid metabolizers. So a methadone metabolite ratio less than four and follow them over their pregnancy at several time points, and then also assess them postpartum. And they found that the number that were ultra rapid metabolizers increased from 8% to 38% across pregnancy, and then decreased down to 5% postpartum. So why does that happen? We know that there's kind of a shorter half-life, larger clearance that, as we talked about, CYP3A4 activities increased, and so you can have more rapid methadone elimination. So I mentioned the serum MMR a bit, and I just wanted to quickly define it for you and just share the study by Dr. McCarthy that really kind of categorized these different groups. So it is the simple ratio of a methadone level to EDDP, which is one of the methadone inactive metabolites. And you compare the level of methadone in her blood at a given time with the metabolite of methadone. Notably, this ratio does not change the timing of a blood drop, so it eliminates the barriers to getting peaks and troughs at certain times, depending on when a dosing window is. And while this lab is not yet widely used in clinical practice, there's growing evidence that it helps us know if people are rapid metabolizers of methadone, and these are the ratios that they presented. So those ultra rapid metabolizers have a ratio of four or less. So here's our case. This is the methadone metabolite ratio for the patient that I presented. These are two different time periods where the levels were obtained, and there was a 4.8 and 3.8 MMR at two different time periods, really kind of putting her squarely within that ultra rapid metabolizer phase. So what does split dosing do? Why do we think it's ideal to offer this to all pregnant women? Because if you are able to sort of reduce that kind of peak dose and also that trough, increase that trough limit for what people are experiencing, you keep them more in this therapeutic range. And ideally all women should be offered split dosing to maintain a therapeutic level in pregnancy. Unfortunately, there's a lot of practical challenges that arise, so a few OTPs offer two dosing times per day. So initially when they're getting stabilized, it can be challenging to find a place to refer somebody to, and then there's the logistical challenge of what it means for a patient to actually go to a methadone clinic twice a day. There's regulatory hurdles for granted take-home exceptions so that that second dose in the afternoon can be given at home. And as I talked about, it can be difficult to sort of link to a program and discharge, which can cause a prolonged hospitalization as it did in this patient's case. So in terms of the case that I presented, this patient actually was able to enter a residential treatment program, but we were unable to advocate for her to get split dosing. And so she remained on a single dose regimen at 315 milligrams because of the sort of regulatory hurdles that were involved. Finally, I wanted to talk about what we're sort of beginning to learn about why split dosing has a possible benefit to the fetus. And mechanistically, I think this makes a lot of sense when you think back to that graph a couple of slides ago, where our goal is to really keep, you know, the therapeutic range in as narrow window as possible. So we want to minimize fetal exposures to both peaks and troughs. And that, you know, a single dose regimen will significantly lower the fetal heart rate. It will reduce fetal monitor activity at peak versus trough and twice daily dosing sort of normalized is those fetal measurements. There's ultrasound documented fetal behavioral abnormalities in a single dose that you can see abnormally increased motor activity before the dose and significant depression after the dose, but those fetal behaviors normalized on twice daily dosing. So I think there's a lot more to learn about the in utero environment and our understanding of fetal stress tolerance, but the evidence is really clear that split dosing is preferred. Jack McCarthy has done such an incredible amount of work in this field in California and really challenged the sort of policy and regulatory hurdles and made amazing strides. I think in our experience on the East Coast is that it just remains a challenge and a huge barrier that is leading to women having kind of worse pregnancy outcomes. Dr. McCarthy's group also performed this retrospective study to understand the effect of split dosing on neonatal abstinence syndrome or neonatal opioid withdrawal syndrome rates, but I think is important and interesting to look at. So this was a study that looked at all pregnant patients at an outpatient treatment program who conceived on methadone maintenance treatment. So they had 78 women who were in their study. So by design, this program had intensive psychosocial supports. There were weekly random urine drug toxicology testing and they did monitor the methadone troughs. They were able to obtain state and federal approvals for daily take-homes that were approved in the study setting and that all patients transitioned to split dosing by the second week that they were in this clinic. There were dose increases for maternal reports of opioid withdrawal and they actually divided the doses not just into BID dosing, but up to four times a day dosing. In terms of patient characteristics in their study, the dose of delivery was a median of 152, although those ranged widely between 20 and 415 milligrams of methadone. You can see that interestingly in the study, which may have been somewhat related to the time of when the study was done, there were the largest percent were individuals who were using non-prescribed prescription opioids and about a little less than a third of them were using heroin. The majority of them had tobacco dependence and actually a very high number of them breastfed. In terms of their results, the primary outcome in this study being rate of neonatal opioid withdrawal syndrome with pharmacologic treatment, there were only 29% of neonates who required pharmacologic treatment compared to 60 to 80% published rates nationally. They found no relationship between the total daily dose and NAS severity, which is similar to what we've seen in the mother trial and other retrospective cohort studies and no unusual adverse effects. So before I leave methadone, I wanted to just talk uniquely about some of the challenges to postpartum dosing. So the first is that maternal function relies on finding the optimal postpartum dose. If you have a dose that's too high, you risk over sedation, overdose, safety issues for the baby. If it's too low, you have withdrawals that can destabilize someone and lead to a recurrence of use. And there's no clear time point for when someone gets back to their pre-pregnancy metabolism particularly for women who may not have reached their therapeutic dose prenatally. I think it's important to note that there is no evidence for blanket adjustment of methadone after birth. So dose adjustment should be based on an individualized assessments with close monitoring or consideration of pre or postpartum methadone metabolite ratios or peak draw measurements. And then there's a real inconvenience to daily dosing in the postpartum period. So think about the immediate postpartum period when an infant is being monitored or treated for neonatal opioid withdrawal syndromes. That daily dosing requirement can interfere with bonding, can interfere with breastfeeding, the sort of core key tenants of non-pharmacologic treatment that we reviewed last week. Post-discharge, it can interfere with sleep, with parenting, with a job, right? That idea that you never wake a sleeping baby, that at 5 a.m. all these babies have to get woken up with their parents to go to that first dosing where parents try to avoid sort of crowds in the clinic. And then there's real maternal fear about bringing a newborn daily to an outpatient treatment program as well as just sort of this internalization of all the stigma around being a parent and not using methadone. As part of some of my ongoing research, I've done a bunch of qualitative work with women to understand their experiences on medications. And this is a woman who is 31, who's postpartum, has opioid use disorder, and is on methadone, and she delivered a preterm infant at 34 weeks. And I think that this quote from her is extremely powerful. She wrote, or she said, "'I have an open wound. "'My body is open, more open than it's ever been "'to a point where it itches. "'Now here I am in the clinic. "'Now this person, he's got open sores "'on all his arms and his legs. "'I'm standing behind him and I've got an open body "'and a brand new baby with hardly any immune system. "'I've gotta now go to the clinic every single day "'with my body, I'm sorry, with my baby "'and hope that whatever this person's coughing "'to the left and to the right of me "'isn't something like pneumonia. "'Why is it that I just had a baby three days ago "'and they were able to dispense me "'of my medication in the hospital, "'but yet I come home from the hospital "'and you expect me to waddle my open body "'with my child in this car seat and carry it, no doubt.'" That sort of speaks to the challenges that people in recovery face and says it more powerfully than I could. Okay, I wanna move on to our last case. Unless there's a question that you think it makes sense to answer now. Yeah, I think there is one question or statement that was brought up by one of our participants here. And he says that there was a big push to get pharmacogenomics in the past, but insurance didn't pay for it. This case of rapid metabolism would have shown up in these patients. And I think it's a good use to not only prove rapid metabolism of buprenorphine, but also historically in patients who required high doses of opioids. Yeah, I would be so eager if you have studies that show kind of rapid metabolism of buprenorphine. I think that we've clinically also seen this too, but from what I have been told, having not sort of scoured this primary literature myself, is that there's no great sort of mechanistic studies around rapid metabolism and buprenorphine the way that we clearly have it for methadone. So please, if you have kind of things that you identified through the work that you've done, I'd love to see it, to be able to cite it and look at it. Thank you for that comment. All right, I'll move on to the last case. So this is a 21-year-old female. She's a G1, and she had a late transfer of care at 31.4 weeks. She self-discontinued her opioids during her third trimester after no program would offer medically supervised withdrawal. Her substance use disorder history is notable for primary opioid. So she's used mostly intranasally, no reported injection drug use, has secondary cocaine and benzodiazepine use disorders. She started using substances at 14 when she was introduced to them by her mother. She transferred to our clinic from another clinic because the patient is adamant that she does not want to be on any medication. She felt extremely pressured at the other clinic to use medication to treat her opioid use disorder, and she declines it for you today. Of note, she's had a negative experience with buprenorphine in the past, having only used it in a non-prescribed way and had precipitated withdrawal when she was started on it at an outside hospital when she had an admission for kind of a complication of her substance use, and has declined methadone due to the daily requirement, fear of dependence. And again, she had previously been on it during detox admission and didn't like the way it felt. She is extraordinarily anxious about potential child welfare involvement, having had been involved in the child welfare system herself as a child and knows that in our state in Massachusetts, that a mandatory report will be filed if she uses medications with opioid agonists during her pregnancy. So I thought this was a good case to think through one of the questions from last week, where one of the participants said, I was taught that detox can be very damaging to the fetus because of potential repeated cycles of withdrawal in the fetus compromising blood flow, oxygen, and other elements to vital proper growth and development. And we were taught detox only under close obstetric supervision. I kind of commented that I wanted to bring up this systematic review that was published in the Green Journal by Mishka Turplin and colleagues in 2018. And I wanted to walk you through some of its findings. So this was a systematic review of the literature that was published from 1966 to 2016. They included studies with reported outcomes associated with opioid detoxification among pregnant women with opioid use disorder. And of the studies that they looked at, 15 met criteria, which included almost 2000 individuals of whom a little bit more than 1100 of them underwent detoxification. I think it's important to note that they did a really excellent job sort of classifying the grade of the evidence. And they graded them ranging from fair to poor due to the lack of a randomized control or even a comparison arm in many of the studies and high risk of bias. The location of detox though is most commonly reported with the inpatient setting or occasionally incarcerated setting with only three of the 15 studies including outpatient groups to kind of note the sort of original question from the participant. Detox completion and relapse rates varied really widely. I think it's pretty amazing to think about the successful completion in these papers range from nine to 100%. And that the relapse to non-prescribed opioids ranged from zero to 100%. Meaning that there just is this huge spectrum of experiences that people had. And I think that really speaks likely to the setting in which detoxification was offered. And then to the sort of commenter's point around the risk of fetal demise, what they found in this study is that fetal demise did not differ between the detoxification group of which 1.2% of those had a fetal demise and the comparison groups of which 2% had reported fetal demise. But yet there's a real sort of important limitation that there was a loss of follow-up in both groups. And so some of the information may not be known. And that they sort of quote in their discussion that the strength of this finding should not be taken as support for abandoning opioid pharmacotherapy as the optimal treatment for use of opioid use disorder in pregnancy. So I think to go back to that initial comment, what I took from this paper is clearly this idea that the risk of relapse to non-prescribed opioids is extraordinarily high and can lead to significant harm to both mom and baby. And that likely in supervised settings, medically assisted withdrawal with the right participant may be possible and feasible but shouldn't happen on one's own doing this kind of in an unsupervised setting for both reasons for comfort of that mother or birthing person, but also potential harm to baby that is still, I think, an area that is important for further explanation. I wanted to offer you from the similar qualitative work, the same qualitative study that I described before, two additional perspectives around prenatal medication use. I think many of you that are listening today are individuals who are prescribing buprenorphine and may be prescribing buprenorphine to pregnant people. These are individuals who actually got their prenatal care and comprehensive care in the multidisciplinary clinic that we run at MGH. We took a step back and really were struck by these comments, including, I'll read them to you. When I got pregnant, I was told by the doctors at the hospital, you can't come off this because you could harm the baby or the baby could die. Not saying this to have an excuse, I really had no choice. I really couldn't. If a doctor was telling me that I could hurt my baby by coming off of it, then I'm not going to come off of it. I stayed on it and I came off all my other meds, but I stayed on that. Particularly the sense that that idea that the reason why individuals have to stay on medications is for harm for babies, that participant commented on is very, very commonly known. I think still the primary explanation is to why people are telling individuals to stay on their medications during pregnancy. Then the second, as I was forced to stay on buprenorphine my whole pregnancy, it was never my decision. I was talking to my doctor about options and I was telling my doctor that I felt fine, that I had to be on some kind of medication to prevent relapse. They still pressured me and put it in my head that it was like the best decision or whatever. I just didn't feel good being on this medication. I did not. I was forced. I felt like I was forced. One of the questions that came up at the end that we didn't get a chance to talk through last week came from a participant who said, I had a pregnant patient on 24 milligrams of buprenorphine who insisted on stopping the medication. Being that the fetus has been exposed to buprenorphine, can we even ethically taper her off buprenorphine while pregnant? I think that this is such a good question. I think our patient's experience really sort of challenged us to think about and then sort of the perspectives of the quotes that I shared with you to think about what does it mean to sort of really offer shared decision-making with patients, to really truly explain to them the risks and benefits. Clearly as addiction physicians, you know the harms to them decreasing or potentially tapering off their buprenorphine in terms of the extraordinarily high relapse rates and risk to baby. But if that is a decision that they choose, what are the ways that we as addiction physicians can better support people so they don't feel like they have to potentially stop coming to the clinic if they're going against the advice that they've been getting or feel like they can't get their care there. So one other question that came up from last week was around the differing NIS or neonatal opioid withdrawal rates based on receiving a buprenorphine monoproduct versus a buprenorphine naloxone product. So Subutex versus Suboxone. And this is a study that I hadn't read, so thank you again for letting me know about it. And I went through it. Oh, this is slightly out of order. I was wondering where this one went. I meant to just include this in the last section. This is a R01 that Dr. Andre Jones at the University of North Carolina at Chapel Hill as well as Sarah Heal and University of Vermont are doing to really understand the maternal, fetal, and neonatal outcomes, looking at medically supervised withdrawal versus agonist maintenance and the treatment of pregnant women with opioid use disorder based on sort of a shared decision-making framework and then an individual conversation with each person to decide what they want, and then they follow them through. And I just wanted to let you guys know that that's ongoing. It started in 2018 and is funded through 2023, and then I'm really eager to learn alongside those really excellent researchers as to what they find. Back to the paper that I told you I was going to talk about now, so the Mullins paper that looked at NAS rates in individuals exposed to buprenorphine monoproduct versus the buprenorphine combined product. So this is a retrospective cohort of studies of patients with opioid use disorder who received their care at a comprehensive program in Western North Carolina between 2014 and 2018, and they included singleton pregnancies that resulted in a live birth who were prescribed either the buprenorphine naloxone combined product or the buprenorphine monoproduct. And I think it's, so exclusion criteria, individuals who transitioned to methadone or crossed between groups were excluded, and also important to note that this program considered the combo product was their first line unless patients were stable in the monoproduct or had an adverse reaction to the combination product and then were offered the monoproduct. And their primary outcome for the purpose of the study was the rate of NAS that required pharmacologic treatment. And what they found is that of the 193 dyads in the study, 108 had the buprenorphine monoproduct in utero exposure, and 85 had the combined product in utero exposure. There were no statistically significant differences between maternal characteristics of the two groups, and this finding that was what one of the participants shared last week is that the buprenorphine monoproduct had 59% of infants who required pharmacologic treatment for NAS and compared to the combined product where only 35.3% of the infants required pharmacologic treatment. So I wanted to just highlight their table three. Again, I think this is where the importance of multivariable model adjusting for confounders that we know that can affect neonatal opioid withdrawal is so important. And if you take a look here, looking at buprenorphine and naloxone compared to buprenorphine in their multivariable model, they had an adjusted odds ratio that kind of confidence intervals crossed one, so no statistically significant difference between those two kind of percentages that were explained in the descriptive statistics. And they comment in their discussion that the odds of NAS requiring treatment were significantly lower among individuals exposed to buprenorphine combined with naloxone at the univariate level of analysis but not at the multivariable level when adjusting for preterm delivery, year of expected delivery, buprenorphine prescriber, diagnosis of hep C, and dose of buprenorphine in delivery. So one thing that I thought was really interesting is when I had hypothesized to you what might be the sort of difference, I said things like co-occurring psychiatric diagnoses or medications that that person's taking or breastfeeding rates or maternal presence at the bedside. And so while those may have differed, none of those were things that were adjusted for that, were included in that model, but ultimately no significant differences, which is, I think, mechanistically what we would understand based on the similarities in the buprenorphine exposures. Okay. And I think this is the last question that came, was shared with me. So in your anteprotein visits, how do you prepare the woman for questions about why the baby is in the hospital for days after delivery? Have women who keep their treatment with buprenorphine or methadone private? And then extended family or friends ask these questions. This is such a good question. Thank you for asking it, because I think you really want to work with families to help them feel, one, that their privacy is going to be protected when they come to the hospital, that hospital staff know, if not everybody in the room, although they should always assume that that information is kept private, that hospital staff know particularly if there's a family member or particularly a father or birth partner who may not know that information to make sure that there's not an accidental sort of disclosure. And I may come up with some like elaborate kind of medical indications if it feels as though it's necessary for that family to keep their medication sort of private. I think my first approach is to sort of really understand why people feel as though their buprenorphine is any different than the medication that they're taking for their gestational diabetes and think about how the withdrawal that the baby is experiencing that's transient and treatable, that's really an expected effect from being on the medication similar to someone who has gestational diabetes who's on insulin, whose baby is at higher risk of hypoglycemia and then may require some additional dextrose-containing fluids and additional monitoring as a result. But if people really want kind of a crafty story around why this baby is going to be monitored for longer, I am happy to sort of come up with that with that patient, whether that's sort of, you know, feeding issues, respiratory issues, or kind of, you know, developmental concerns, but usually we come up with some feeding or respiratory issue if it really is absolutely a need and desire to keep that secret. Okay, I think that's it. Sorry, I talked a little bit longer, but it looks like there's about 10 minutes and welcome your questions again. Okay, thanks. That was a great review of a lot of new stuff in addition to some questions from last week, so thank you for all of that. We do have some questions that we didn't ask during the presentation and the first one is, the policy where I work requires a switch from buprenorphine naloxone to buprenorphine monoproduct for pregnant patients. What's your opinion about the concern for using naloxone in pregnancy? Yeah, we talked about this a little bit last week and some of the evidence behind it. I now think that there's significant retrospective evidence that should allow you to go to kind of your hospital guidelines policy crew to say that there's no fetal harm that's expected from naloxone exposure. And we reviewed that some of the potential benefits of continuing individuals who are stable in their medication, who are stable on the combined product, is that there's both in the prenatal period, but specifically in the postpartum period, there's no risk of kind of difficulty transitioning to a new medication, sort of being one important piece. The second is that I think there is potential risk of diversion when you're switching to the buprenorphine monoproduct that you don't see with the combined product. I think we've seen no adverse fetal effects, so I would sort of challenge them to say, you know, we did this because this is what was used in the mother trial, and so it's thought to be kind of the right medication. But I think since then that group has also published studies that have shown that there are no adverse fetal effects from using the combined product. Next was more of a comment saying there are recommendations in earlier treatment improvement protocols from SAMHSA that it may be done, I'm thinking, medically supervised withdrawal, mostly in the second trimester with close involvement of the OB and use of non-stress tests. Yeah, would support sort of medically supervised withdrawal if you and your patient decide that that's in the best interest of them. That sounds appropriate. Next question is, is there any work being done to address the barriers to accessing methadone through an opioid treatment program while also reducing the risks of methadone overdose or diversion associated with extended takeout doses for someone who may be continuing to use or living in a situation where they may not be able to safely store medication? Yeah, this is such a good question. I think we're going to learn a lot from data that's being analyzed around the COVID pandemic. I think in a lot of ways we learned that the very quick shift to reducing those regulatory barriers in the setting of the pandemic that gave people up to a month of take-homes at one time didn't see that sort of skyrocketing, skyrocketing rise in overdose deaths that we have been sort of forewarned about. And I think that data will be really important to sort of making the case for reducing some of the federal regulations at this time. Further, I have a dream that I really would like to see us offer to all postpartum people, whether you're a birthing person or the supporting partner, to sort of have a postpartum methadone parental leave where I really do think through either supervised telemedicine visits or a visiting nurse, we can figure out how to get your methadone to you so that you're not waking up at 5 a.m. every morning to get to a methadone clinic in that immediate, disorienting, totally exhausting postpartum period. But that's my own wish list. Vanya Rudolf at ARS Swedish, I think I mentioned her last time, is just a trailblazer in this field and she's been working really hard at the state and national level to think about, specifically in pregnancy, the barriers and regulations to things like split dosing, the things like take-homes. Why was the patient who was on sublocade switched? Was it purely medical-legal concerns? Yeah, thank you for bringing that up and I think it allows us to have a little bit more of a conversation around something that came up in the question and answer session last time, which is, what do we do for a patient who's on sublocade and becomes pregnant? This is a patient who actually transitioned to sublingual buprenorphine in the context of enrolling in a randomized clinical trial. So she really, really had stabilized well in her sublocade and was hoping to sort of randomize into the arm that was going to continue an injectable buprenorphine product in pregnancy. So I think what we know about sublocade and in kind of animal studies is that there is an excipient in the kind of medication that was found to be teratogenic in animal studies. And so that's why it's not recommended at this point for use in pregnancy. And there's a randomized clinical trial called the MOM Study that's based out of the University of Cincinnati and the National, the NIDA Clinical Trials Network, that's looking at CAM-2038 or BRIC-SOTY, which our site is part of. And so this person was actually trying, hoping to get into that injectable arm, but she went on to the sublingual arm. And honestly, as a result of her experience, we've thought really long and hard about this idea of how when someone's stable, you don't mess with their stability. Because I actually think the fetal risks of harm that happened from this patient who had been stable on sublocate on an injectable buprenorphine to when she transitioned to sublingual buprenorphine were certainly exacerbated by that change in the medication delivery. We have one question, can naltrexone be used during pregnancy? Yeah, great question. It is being used in pregnancy, I think, similarly to sublocate. There's actually another study that's looking at kind of the pharmacokinetics of naltrexone and the sort of fetal and maternal effects of naltrexone use. I think we know a little bit more about oral naltrexone, but certainly Vivitrol use in pregnancy. And similarly, I think our clinic's approach right now is if somebody comes to you who is on that medication, has been stable, it's been supporting their recovery, and they become pregnant, that we wouldn't recommend changing that medication away and risking their stability and recovery. One question about one of the studies you talked about in the buprenorphine and buprenorphine naloxone trial, what was the average buprenorphine dose used for the pregnant patients? And did the doses vary from the model products or not? That's a great question. I might even just have it up while I can answer that question for you. I don't remember it off the top of my head. There's a buprenorphine between the two groups. So they classified this, they list the median, and there actually were significant differences. Thanks, that's a really good question. So the median in the buprenorphine monoproduct group was 16 milligrams with a range of 10.5 to 24. And in the buprenorphine combo product, the median was 12 with a range of 8 to 20 with a p-value of 0.02. So slightly different doses of buprenorphine as well. I think that kind of comment is important in the setting of there have been some studies that have shown more severe neonatal opioid withdrawal with higher doses of buprenorphine, which again, is really different from what we've seen with methadone, which is that higher doses of methadone are not correlated with higher increased severity of neonatal opioid withdrawal. So I think that was a well thought out question and an important point, and I think something we'll continue to learn more about as more people are treated. We have one minute left, but I want to get to this one question. Clearly, many of your patients are using multiple substances, in one case, not daily. How are you documenting these outliers and their treatment for the other substance use disorders? Yeah, it's a really important question, particularly because I think, honestly, we're seeing so much more stimulant use. We're seeing such a rise in methamphetamine use in the area where I live in New England. We try on admission to do a really thorough history of sort of what their most recent use was and when, and probably we need to do a little bit better job of systematically categorizing the frequency of use and what the exposures are. So I'd welcome suggestions that you guys have and what has worked for you and your practices for thinking through those co-exposures as well, both from a clinical standpoint and also from a research standpoint, because I think this is where it becomes so challenging to really sort out the maternal and fetal and then infant neurodevelopmental outcomes from certain exposures when we say focus so much on a medication treatment and know much less about those other co-occurring exposures. Thank you for that question. Just one last was a statement or a question, I guess, about split dosing and not in the legal issues that disallow for that. And I believe that's around state regulations typically. Can you comment more on that? Why some places can't do split dosing for pregnant women? I feel like this is a much longer answer to a very important question at the buzzer. I think there are both federal and sort of state regulations that sort of make certain requirements in terms of take-home doses and split dosing. And I think they vary by location. And so I feel like it would be most important to sort of consult your local regulation and then they will tell you better than I'm going to be able to tell you right now. Yeah. Okay. Well, I'd like to thank you again for this webinar series and thank you for all of our participants who've been participating over the last six weeks and really engaged with their questions and in the discussion of these webinars that we've had. So thank you again, Dr. Schiff, for presenting today. And this is going to be the end of our hot topics for this year, but we are looking forward to having a webinar series again next year. Thank you.

Treating Opioid Use Disorder in Pregnancy

Perinatal Period

Dr. Davida Schiff

Buprenorphine microdosing protocols

Methadone metabolism during pregnancy

Benefits and risks of split dosing

Maternal-fetal risks of medically-assisted withdrawal

Individualized care for pregnant women

Close monitoring and support

Accessing methadone treatment