 Thank you so much for having me here today, Dr. Kess. Thank you for the invitation. I'm really happy. It's the first time I've ever come up to this medical center to upper Chesapeake. We receive babies from here all the time and it's really nice to put a face to the people I work with. Talk to them on the phone just to meet you and get to know who talks about the phone and who runs the transports. So it's an endemic, it's an epidemic, endemic problem. But it's more for me today to share experience with you as well because I really think those babies should be in the community. And I tell you why. I have nothing to disclose. So what are the objectives today? Today mainly I just want to make sure at the end of this presentation that you guys recognize the expanding problem of the illicit drug use, not only the illicit drug use but even the problem includes mothers who are on treatment programs. It's still an NAS baby. So this problem is nationwide but how big it is in Baltimore. Determine the magnitude of NAS as a problem in the NICU at the University of Maryland. Medical center to relate to the pitfalls of NAS screening and scoring system. Identify pharmacological and non-pharmacological interventions. Detect the long-term outcome and engage into the NAS Maryland training collaborative which I think is one of the excellent things that's out there for us. So to start a little bit of a schematic diagram to show exactly what happens with addiction. So the Mesolymbic dopaminergic system originates in the VTA or the ventral tegmental area. It sends information from this VTA area into the nucleus accumbens. And from the nucleus accumbens the information travels all the way to the prefrontal cortex giving the sense of reward or satisfaction or the pleasure that they get with addiction. So it originates here, travels there. So what makes it travel? Well actually the neurons are under continuous suppression by GABA. So this is in the VTA and the GABA actually does suppress any sense of pleasure or reward. Not any sense but the ones related to extra sensations. It does occupy the receptors and prevent this kind of reward or positive reinforcement coming sensation all the time. So when a patient or a baby is exposed to morphine or morphine derivative, any kind of opioid, what happens? It actually causes hyperpolarization of the receptors. And when this hyperpolarization happens it opens the way to the dopamine to travel from the TGA all down to the receptors in the nucleus accumbens. And there it occupies the receptors, the post-synaptic receptors. And it travels all the way to the motor cortex, the prefrontal area giving the sense of reward or satisfaction or actually pleasure. So Baltimore. I like to stop at Baltimore. Maryland has a population of around 6 million individuals, a population of 6 million. 10% of this population they are located in Baltimore. So Baltimore is have a high rate of non-employment and also have a high rate of poverty, one in four are below poverty line. So how big is the magnitude of the problem in Baltimore? The National Institute on Drug Abuse have its latest report in 2013 and this is the report that is shared with public. And looked into data from 2009 all through 2013. And you could see here again big problems and this is for Baltimore City and it will be coming to Maryland in few minutes. Marijuana use is definitely a big problem, persistent problem. Heroin is another one I want to stop and say a word about. Although it looks as if it's been steady, but it's not. It's been on the rise since 2013 and there is more and more use of heroin in Baltimore and in Maryland in general. And also the other group I would like you to pay attention to for my talk is the oxycodons which are the pain relievers, whether they are oxycodons, tramadol or all of this group. So I have an emerging problems or an increasing, a trending, a problem of heroin use of oxycodons and a persistent problem of marijuana. And I'll come to this to talk more about marijuana. So what is neonatal abstinence syndrome? It's a group of problems that occur in newborn babies who are exposed to addictive opiates. It has to be opiates. NAS is not a problem of marijuana, it's not a problem of PCPs. It is just opiates. And if the fetus is exposed to opiate in utero, then that causes the problem once they are born because they get into withdrawal symptoms. They had a certain level of opiates, they withdraw from it because it's not there anymore. It probably involves the central nervous systems anyway from tremors and shaking all the way to seizures. And the autonomic system was instability of the respiratory and the cardiovascular system as well as the gastrointestinal system. It could be called NAS or neonatal abstinence syndrome or withdrawal, neonatal withdrawal or withdrawal babies as the common term is in many nurseries and NICUs. You all know the drugs that are associated with withdrawal. So the first column here are mainly those causing withdrawal. Opiates comes on the top. Benzo, benzodiazepines, also a very important group does enacts and other benzos. Antipsychotic drugs, especially the SSRIs or the slow serotonin reuptake inhibitors, ethanol and all other drugs. Well, if you come to nicotine, cocaine, marijuana, they cost toxicity but they are not actually by themselves. They would not cause neonatal abstinence syndrome. This being said, they are very important in the escalation of the problem and I'll come to this again very shortly. So what causes neonatal abstinence syndrome? It is the use of illicit medication drugs. They could be morphine, heroin, they could just be illicit or even those drugs that are prescribed for the treatment of maternal opioid. Some others who join the treatment programs, they are given methadone, they are given buprenorphine. So those also are opioids and the babies will still have the same NAS problem. 6% of pregnant women use illicit drugs. Almost half a million of babies every year are exposed to those drugs and 40 to 90% of those exposed to opioids will develop neonatal abstinence syndrome. So why is it on the rise? It is on the rise and why is it on the rise? For the liberal use of prescribed opioids for pain, all the codeine group and tramadol and other similar pills and medications, the illicit use of new opioids such as the heroin and the TH. The TH are the cannabis homologues or the marijuana, the synthetic marijuana. This is a very dangerous group and this is really, this is invading Baltimore. And this is problematic because it does not show on testing, on toxicological tests for urine. So those who do not want to be caught with a positive urine sample or a positive toxicological test, they start using those drugs. And those drugs are not like marijuana, those drugs are really toxic. They are a different animal. They look like amphetamines, like the person who would take them would be agitated and sweaty and angry and aggressive. It's not the mellow, funny person on weed. No, this is a different person. And it is 100 times more potent than marijuana. And actually it has a big problem because marijuana is a natural herb. It does contain cannabinole. And this breaks down or decreases the adverse effect of marijuana. When they go on the synthetic herbs, it doesn't have it. So they get a full blown picture of those symptoms. Not only this, but they are a full agonist of the receptor and I'll show you this again in a few slides. So the use of marijuana, the dramatic increase in opioids substitution programs for the treatment of opioids. The shift to drug use from inner city, the classic low income inner city, Baltimore, it's spreading everywhere. So it's been a diverse problem now. Talking about the enrollment into treatment centers, the first graph here presents Maryland and the second one is Baltimore. The first one, just to show you the primary enrollment in the last, in six years, from 2006 to 2013. And one thing I want to point out. If the population of those on drugs or enrolling, not on drugs, enrolling for primary enrollers for treatment programs is around 18,000 in the whole Maryland, it's 50% for Baltimore. So although Baltimore comprises 10% of the population, but it is 50% of the problem. And you could see this easily when you come to emerging medications, drugs as heroin. You could see 8,000 when heroin for the rest of Maryland is around 14,000. So it's more than 50%. Again, I would like to point out the other opioids like the oxycodone, these are all on the rise. So what determines the severity? Why is some babies just drawing and other babies are not? Well, it's multifactorial and it's very complex. One of them is what is the baby was drawing from? Opiates 50% plasma bound, crosses the placenta readily, and it is uptaken by the fetus in a matter of two or three hours. The benzos is another big problem that we face. And it's again, it's on the rise, trending up, and they are very highly lipid soluble. They are ionized, which means they get into the placenta easily. The dosing, how much are the mothers on? Even if they are in the methadone program, how much are they taking? And the timing of the last dose or the timing of the last, when they had the drugs the last time. And for how long the duration was it just like a one-time thing? Of they've been taking it through pregnancy. The gestational age of the baby and the weight, the infant metabolism and genetics. And genetics now is a really hot topic and I'll be addressing soon. And then polysubstance abuse that I started talking about. So although withdrawal and NAS is a problem of opioids. So what about marijuana? If it doesn't cause, if it's just a toxic medication or toxic drug. Well, it does. If you go to this graph, marijuana, more and more research is coming out to show that the cannabinoid exposure authors the neural circuits responsible for the opiates, abuse and for the withdrawal. So it actually overlaps with this opiate here, the CB1 is the cannabinoid one. So this receptor or this in the brain overlaps with the opioid receptor. Causing augmenting the effect of pleasure and augmenting the withdrawal as well. So being an opioid alone or being a methadone alone is one problem. But if they are a polysubstance abuse it's a bigger problem because there is kind of augmentation. And going back to the CB1 or the cannabinoid receptors, it was classically known to be in the prefrontal area. But this is not true. It's everywhere in the brain. It's in the hippocampus where it's responsible for memory. It's in the parietemporal lobe where there are areas that if triggered too much they cause seizures. It's in the brainstem and that's why you get respiratory and gastrointestinal symptoms. So marijuana, especially synthetic marijuana or cannabinoid, mymatics are a large problem. And I consider it as a very bad problem causing mortality among Baltimore, in the Baltimore and in Marin, for whatever users are using it, but actually it's augmenting the problem for our NAS babies. Not to mention legalization of marijuana, medical marijuana, that's a whole different scope. So this slide here just wanted to show you the effect of opioids on the brain volume. So they looked at 16 babies, NAS babies, was growing from opioids and they had MRI with volumetric analysis to the weight of different parts of the brain. And one of the parts that was really decreased in size was the basal ganglia. So they looked at babies, the sample size is small, but they looked at babies who were only on one opioid, like methadone is included, versus two opioids, which means methadone, heroin, methadone and morphine. And they found that the babies who are only on one, babies are only, this is the gray box here, are babies the weight of the brain of the basal ganglia, if the baby is exposed to one opioid, versus if the babies are exposed to two opioids. Which is, again, the sample is small, I don't know how much we could take from this, but it's a warning sign, because if it is two opioids, you are getting a decrease in the brain size, and thus a definite neurodevelopmental problem afterwards. So that's toxicological screening. So how do we know that the mom is on any drug? They disclose the drugs. I actually looked into, and I'll be sharing this with you, 10 years of NAS in our NICU, moms disclose it. I had no problem, I had no mismatch between disclosure and our toxicological tests, whether for the babies in the NICU or for the mothers. So what do we use for screening? We use urine. There is no consistent policy on what to use for screening. We use those eight drugs for screening, and recently we are in the process of adding buprenorphine. So we'll be screening for nine of those. So urine is fast. It's easy. It actually does reflect or measure fetal exposure to addictive drugs in the last few days, maybe a day or two. It will give you a long term. It's a radioimmune assay. It has to be the first sample. So if the baby peed on the delivery table, you're losing the concentrated sample. You're getting a diluted one, just because you're waiting for the baby to pee again. So it could be enough time for the drugs to clear from the urine, or it's just so much diluted that you're not going to get the right thing. So what about meconium? It detects, again, fetal drug exposure from the second trimester, but you need a good amount. You need at least 50 grams of meconium. You have to store them in the right temperature. It can be regular freezers. This has to be minus 20 to minus 80. It is analyzed through solvent extraction. And if the baby passed meconium, it's irreliable. For some reason, it's irreliable, because if they passed meconium, I mean in neutral, you might not get a significant or reliable result. Hair could detect fetal exposure to drugs from the third trimester. You don't really have to pull the baby's hair. You could just cut it so close to the scalp. You need 20 to 50 milligrams of hair to do this. You could do it at two months, at three months, when we have CPS involved, and we have this concordance between our talk screens, mother history, and how the baby looks. We ask for this, and we get hair analysis, and it's always positive. So you wonder how many we are losing, or we are not detecting. Cord blood, remember, it's the least sensitive, because the dilution of the drugs in blood is so low. So it's not something that it is recommended. Opioids, generally speaking, they take one to three days to show, the babies would take one to three days to show withdrawal. Heroin is the fastest. It could happen in the latter of hours. There is differences, but I think also there are overlaps. So you could say heroin would mainly give neurological manifestations with tremors, high-pitched cry, buprenorphine is mostly GIT symptoms where the reflux and the poor suck and swallow, methadone, mainly sweating and temperature instability. But I can't draw a line. I've seen it all. It is not line drawing. It's just, it could come in any picture. So a very sad but true statement. Every 25 minutes, a baby is born suffering from opioid withdrawal. So I'm starting now to share our data from the NICU University of Maryland. We looked back at 10 years worth of data. Went through the charts, took us like maybe a year and a half to clean those charts because there was a lot of ayatrogenic withdrawal that we had to filter away and just to focus on those that are related to a nutrient exposure. So if you look at this graph here, and these are babies more than 34 weeks. If you look at those ones, the blue line represents any baby that came to the NICU who was exposed to either illicit drugs, any kind of illicit drugs or to methadone buprenorphine. So any kind of an addictive drug. And look at this, a striking increase over the last 10 years. And if you look at those, and the red line here is just for the actual NIS babies. And we started at 10 babies that used to be in the NICU and we are more than, these are like 57 babies here, 60 babies of our NICU admissions. This is a big number that consume, that they occupy beds and they stay for weeks in the NICU. And this is also on the rise looking at the 2017 data. So what are the medications causing the NIS? So number one medication is domorphine or the opiates in general. And when I say opiates, I am actually coupling all together including methadone and treatment programs. So this would be number one in the blue line. And then follow this is the red line here and this would be the use of marijuana. And we said there is a synergistic effect with both of them together. And then come the others. I would like to point out the purple line here which is on the rise, it's the benzos. And benzos, they are a problem. They do not respond to diluted morphine into the methadone. Actually you treat benzos with benzos. That's how we realized it. We find the baby staying in the NICU for such a long time. It's been three weeks. They are still on the medications. You start at a van within few days the baby is better. So we've been actually paying more attention to this history because they are associated with a longer length of stay. So exposure to opiates. This is just opiates. Again all kinds of opiates. Two things I want to point out. The green here is moms who are in the treatment programs. Methadone and buprenorphine. Prenorphine is not much. It's mainly methadone. And the red are the heroin. So we are having more and more heroin use. And looking here at the blue is the oxycodone. Or trivadone and derivatives of pain medications. So those are on the rise. They were hardly there before. And heroin is appearing. And methadone. It's quite a problem for babies with NAS. So what is the national data? What is out there? So New England Journal of Medicine published in 2015 an entrepreneur article on the magnitude of the problem in 300 NICUs nationwide. This was the Pediatrics Group. And they looked into babies more than 34 weeks. So what did they find? NAS increased from 7 to 27 cases per thousand admissions. Over their 10-year study. Walking increase from 7 to 27. Medium length of stay increased from 13 to 19 days. Pharmacotherapy from 74 to 87%. Amorphine is the most used drug. So what do we have? What did we find in the University of Maryland? We found that the blue bars are babies with NAS. And the red bars are those with NAS that has been treated. So these are not exposed. These are actually NAS. That we started a Finnegan score for them. And they were admitted for at least five days. And you could see two things here. There is a six-fold increase in NAS babies over the last decade. And there is a ten-fold increase in babies requiring treatment to almost 80% of the babies with NAS will be getting a treatment. So if we compare ourselves to the national data, you could find here, look at the blue line. And the blue line shows you the admissions per a thousand, the cases per a thousand NICU admissions. And we went from 17 to 87 cases per a thousand admissions. Just to remind you of the national data or the national average is from 17 to 27. We are three times more compared to national data. Outwards, coming from the community, they comprise 20% of our NAS babies. Still quite a percentage, but 80% are coming directly to us. This is an interesting graph. Just stop there for a minute. I'm looking at addictive drug exposure, NAS, and race. If you look at the first graph here, maybe it will make it easier. Two-thirds of those exposed to any illicit drugs are black NAS babies. Black babies, not NAS, black babies. So exposure in blacks are two-thirds that of all exposure. But actually the ones who develop NAS, it's reversed. Two-thirds are the white race. So there is a kind of vulnerability to those drugs. It looks like there is something genetics that could be coupled to race. That although the exposure is three times more among the black population, but the ones withdrawing are whites. This being said, I have to say that this is a retrospective study. I did not correct for maternal medications how much those parents, there's a lot of confounders and those are one of the drawbacks of retrospective studies. Length of stay is anywhere between two to three weeks. It could be a month. Interestingly here because it goes with our data, the purple ones here are the ones with benzos, and it looks like if they are on benzos, they are staying more than, and these are all NAS babies, but if benzo is included, they stay longer. Length of stay in our NICU, I am looking at eight years from 2009 to 2015, a steady rise from five days to 15 days of stay. So even our length of stay, not as high as the national average, 19 days, but still it went up three times. So more analysis for the characteristics of prolonged length of stay. So what makes a baby stay longer? And again with the caveat that this is retrospective study. So gestational age and weight. So the smaller the babies are, and this is 34 to 37, it's not seven, they actually have longer length of stay. So 34 and up to 37, and then the other babies are more than 37. So if the baby is less than or equal to 37 weeks, they stay more like 14 days compared to 11, and this difference is statistically significant. Another thing that came to be positive was benzos. We're talking about this. We had around 52 babies on benzos, and the sample was, NAS sample was 304. So the rest of the 252 didn't have benzos, but those who were exposed to benzos stayed an average of an extra two days in the NICU. Another significant finding. No difference in length of stay when it comes to gender. There's no difference even to race. I talked how it is really, I thought like all those white babies are withdrawing, but for the length of stay it was the same. So there was no significant difference statistically. And no difference for outborn versus inborn. And there is also striking finding in this retrospective study. No difference if they were only on methadone for the length of stay versus method polydraga abuse. And look at the numbers. And I didn't really stop at this. I didn't go for further analysis. Only 38 of the 304 had methadone only and 266 admitted or ontoxicological studies had poly substance abuse. So what does this say? Even the mother is in a methadone program. She is still using other drugs. Rate of NAS for our NICU, what it means for us? You can see these are NICU admissions from 2007 all the way up to 2016. And the red bars are the NAS babies admitted to the NICU and we are on the rise. We used to be like for NICU days attributed to NAS. We used to be like half a percent and now we are more of a six percent. So this is our data, which is really quite striking looking at it. It is also very unsettling to know that this is going on. Genetic implications. This is the hot topic of things. This is looking into genetics. So what do we look at? So we have all our information and what we know from the adults. Fifty percent of risk of opioid addiction is due to genetic factors. Why someone gets addicted and the other one does not get addicted. It's environmental, it's genetics, it's person's behavior as well. So what are the special genes we are looking at? It just like makes sense if you think what should we look at? We look at alleles or genes in the opioid receptors themselves. So what make the opioid receptors more receptive to morphines or to opioids in general? So this would be one, which is the mu receptor. There is the kappa and there is the delta and the mu, but the mu is the one for the opioids. And then looking at the dopamine clearance. Dopamine is the neurotransmitter causing this sense of pleasure, correct? So if it's not cleared well, there is an enzyme responsible for its clearance. It stays there and it gives this sense of pleasure. But if we treat and the dopamine is not cleared, so it's really counteracting our treatment. Multidrug resistance has to do with placental gene, it's a placental gene transporter gene. And it shows you, it's really what does, it kicks the, so those transporter genes if it makes, it rings any bell. It's what makes cancer patient resistant to chemotherapy. Okay, so this transporter protein kicks out the drug. So they were thinking, could it be some mothers that have those transporter proteins kicking out the opioid? That's why their babies do not develop NAS. But up to my knowledge, and until I searched the literature yesterday, they couldn't find a relation. Other ones are actually the breakdown of methadone that you are giving to the babies, you are giving to the mothers. So this happens in the liver, the cytochrome 450. So if it is actually inactivating the methadone, then the mothers need more and more and more methadone. And that's why some moms are on 20 milligrams and some moms are on 40 milligrams. Is it that she really needs that much or is it that her body is reacting this way? So it's a new era of looking into this. And these are just some of the studies that show variations in the opioid receptor gene on the COMT1 that is responsible for the degradation. And it is very complex because, well, COMT, if you have less COMT, you are more vulnerable to pain like in children, in pediatric children. If they have less of this gene allele or polymorphism in this gene, they need more medications for pain. And it's the same thing when it comes to addiction. And it depends on where the mutation is or where the polymorphism is. So this is a SNP array, so single nucleotide polymorphism. And we look exactly at where what's missing and try to make associations. Our numbers are not big and the literal numbers is not big. Plus most of those studies are on white population, which I think is very reasonable. But we are starting a big study now looking at a population that is 70% black. We are going to see if they have the genes that protects their babies from developing NAS. So the study just passed from IRB two days ago. One of our fellows is working in it and I think it will be very promising. And other, we talked about the transporter protein in the placenta COMT, about the cytochrome 450 or 2B6 and other receptors, opioid receptors. Take home messages. The take home message is actually coupling of the SNPs finding with the baby's pharmacologic and toxicologic profile could be a start of a genetic blueprint to what's happening. So if I find this kind of profile that makes sense why this baby's been in the NICU for 23 days. While this is absent, so that's why the baby's been off medications, observed for 48 hours, symptom free, went home in six days. So it is really, I do not think we could do anything about it because we are not altering genes, but it just helps more understanding of what's going on. Scoring system, I'm not getting to this. We use the modified clinical version from the AAP in 2012. It is the same, the central CNS, the autonomic and gastrointestinal sections. It's scored out of 40. I've never seen a 40. I've only seen one baby seizing from withdrawal. So actually the highest I've seen would be 16 or 18 when they come to us. So what about scoring? Is scoring an issue? It's a big issue. How frequent are we scoring? So a baby is sleeping, you're waking up the baby in three hours to score him, and then he's crying and pissed off and you're giving him a score of 12. That's what happens. Okay. Did you feed the baby and score or did you score the baby and then fed the baby? What about the scoring itself? So this is from AAPC and this is an okay chart, NAS chart from AAPC, but actually I want to tell you I was once rounding and I found this baby, this one baby that got scored for tremors disturbed, scored again for tremors undisturbed. If tremors undisturbed, you don't score for disturbed. If the baby is already having projectile vomiting, you are not going to score for a regerge, because he's having the highest symptom already. So you don't go back and give him a two or give him a three that adds to mind. When I'm talking into, really I'm looking into very narrow, because we start our medications with scores of nine, two of nines. So if you are driving this nine to an 11, I'm already adding my second line medication. So this is a place, this is an area that needs a lot of attention. Inter-rated variability, the rating is, nurses do our rating and they score it in epic every three hours. And this is a study from Columbus, Ohio, that looks at the scoring for the nurses prior to an intervention educational program and posted in the workshop. And you could see here how flat the curve is and you could look, scores could go anywhere from four to 18. And then when they gave them the workshop, the scores actually, you could see how this narrows and goes up and the difference was really significant. If you look at the scoring, you might see, oh, the mean was 13.8 versus 12.1. What I tell you, it is this one or two in the scoring system that makes me add a second truck or that makes me prolong the first one or increase the dose of morphine. So actually an inter-rater observer or inter-rater or inter-observer variability is recommended to be above 90%. And it's an area that we could work in and make it better. Breastfeeding, very important, important for everything. One thing I want to point out, because nurses come to me and say, I'm not going to feed the breast milk because mom is a mother donor. I personally feed. So the recommendation of AAP is the old recommendation not to feed if the moms are on more than 20 milligrams, but they changed this and they said methadone is compatible with breastfeeding after they previously were against it. And then the Academy of Breastfeeding had two criteria. If the mom is already participating in a substance abuse treatment program, she can give her breast to the baby or if she's abstinent and she should be abstinent for more than three months. Sometimes if I see the moms in the rooms, I let them breastfeed because I want to encourage them to be there. I don't want them to feel there. They already feel guilty and they feel bad and we know how genetics really play a major role that's beyond them. And I look at WHO, the World Health Organization, recommendations. Drugs are not one of the absolute contraindications for breastfeeding. So it's kind of, let's see how it goes. But I want to tell you, my nurse practitioners tell me the moms breastfeed so that CPS would not take the babies away from them. I don't know, but it's a good point if that's why they want to breastfeed because this is how they keep their baby and if this is a way to get around CPS, I don't have an answer. I take it one by one. I speak to mothers and I make my decision in video lives. Pharmacologic interventions, first line is oral diluted morphine. We all use it. One thing I want to mention about it, it does have alcohol as an recipient. If you're giving the baby 0.3, 0.4, 0.6, we have babies on 0.9. Every three hours, that's eight times. How much alcohol are you giving to this baby? So I just want to remind you that 20 milligram per ml is alcohol free. The two and the four ml per, per milligram per ml are the ones that has the alcohol. Methadone is a synthetic opioid. It's a full mu-opioid receptor agonist. Have a longer half-life type, 32 hours, up to 60 hours actually. So could be given once a day. Benzos, as I said, benzos for benzos. Nothing else for benzo but benzo for benzos. Buprenorphine is a partial agonist. So methadone is a full agonist. Buprenorphine is partial. And that means just for you, the one big difference is it has a sealing effect. What does the sealing effect means? You could keep on giving methadone as high as you go in the methadone. It has a higher effect. But the buprenorphine, no. It seals at a certain dose and it doesn't make, regardless of how much you give. So in a way it's good. But if this baby isn't exposed to very high doses, it's not going to keep him within target scores. And if moms are really heroin addicts and very high opioid exposure as well, it might not work for them. So it has to be tailored. Also it has the advantage of displacing the opioid. So if mom takes it and goes for a heroin, it displaces heroin. It doesn't make heroin work. So this is a big plus. And it prevents other opioids from binding what it binds to the mu receptor. So this is another great advantage. But because of this advantage you want to make sure it's preceded by 12 to 24 hours of abstinence. Otherwise the mom will go into withdrawal. The mom or the baby will go into withdrawal symptoms. We don't use buprenorphine in our NICU, but something to look into. It is combined with naloxone because moms have been using it IV. So they combine it to naloxone to avoid IV use because they withdraw very badly. They would not do it again. Less length of stay with the buprenorphine compared to the methadone. And even the sublingual buprenorphine is associated with less length of stay for babies. Another, this is from the Maryland, from the Yvonne NIS collaborative modules. And this is the mother's study. And I just want to show here, it's two messages really. The first one that there is no difference between methadone and buprenorphine when it comes to using Baileys neurodevelopmental tool when it comes to outcome at three years, 36 months. The second is actually the scores are really high. Personally I do not think Baileys is the best tool to assess neurodevelopment for babies exposed to opiates because those babies have problems and repeatedly they are not seen on the Baileys. Second line of treatment, we use the clonidine. It's centrally acting alpha-2 adrenergic. So it's sympathetic. What does it do? It lowers the norepinephrine. So you get fewer action potentials and decrease the opiate excitability and thus withdrawal. Phenobarb, we've used this before with pedagogics and pedagogics is 45% alcohol. That's why we're not using it anymore. Half-life is extended to 100 hours. It could cause CNS depressions and it does impair the sacrafiax. This is what we use in our NICU and I would be happy to share this protocol with anyone. It just shows that we, clonidine, we start with a diluted morphine and clonidine is our second line. We start when scores are above 9 times 2. We start by 0.2 of the diluted morphine and we go up if the scores are still at least above 9. Morphine is not weight-based. It's just what we're given. The babies are very comparable to weight, but the clonidine is. What about outpatient pharmacotherapy? You can, Ireland, actually 30% of units are discharged as an outpatient. They start treatment in patient and then discharge the baby on medications. It's more and more into the USA now. There's a combined versus, this is one of the studies I thought was interesting. They treated the baby first in the hospitals, which is the combined and then they sent him home with a once a day methadone. They showed that there was a decrease in duration of a length of stay, of course. However, there was no difference in the cumulative methadone used, those used. So you're really still exposing the baby to the same amount of methadone and you wonder what are we, if we are adding to the damage that happened. Non-pharmacologic interventions, all institutions have tried everything. Mother rooming in, would be the best, can we do it? I think there is, in Baltimore I could speak for this, cultural barrier like moms would not stay regardless of what you do. You just try to be nice and tell her that she's welcome. I think it worked somewhere in I think in Vermont. Was it Hitchcock Dartmouth? No, Hitchcock Dartmouth. They have a special word, but I'm not sure if we could duplicate this experience everywhere. At least not for now. Encourage your breastfeeding, adequate nutrition, increase the frequency of feed rather than the volume of feeds. Music therapy, massage, swaddling, quiet zones, gentle handling, the pacifier. Skin care also to minimize the discomfort with the diaper rash, positioning and some actually use lactose free formulas because of the intolerance to the regular formula. So we, there is a recent study on a vibrotactile simulation mattress that you put there and it kind of swings the baby and it provides vibration and it provides motion. They didn't look into outcome, they just looked into reduction of movement activity. We use the mammaroos, I don't know if you have them here. They are really great and together with the cuddlers we try to have them go into the rooms and swaddle the babies. So about brain growth. Brain growth, it is affected because of the opioid growth factor. Milation is a problem, apoptosis increases, oxidative stress because of the high concentration of neurotransmitters. All data shows there was low cognition at 12 and 18 months, which the mother study does not show. There are deficits in motor function, there are deficits in memory that are recoverable. However, I would like to share this one because it's very important, this is from Australia and they looked at students at third grade, fifth grade and seventh grade. So three grades of follow up and they use the nap plan which is a national assessment testing for literacy and numeracy. And those are the babies and these are the average scores and it's a national test. Babies who were NAS babies at newborn period and those are the match control and these are other children who are not NAS. And you could see the difference of course. And then those who do not meet the minimal standard which is 350 from 1000 were NAS babies, males, low parental education and the native Australians. One third progressed to criminal activity. Is it environmental? Is it drugs? Is it genetics? We could debate this and we could have long talks about it. Those who were exposed to cigarette smoking and marijuana, their offspring actually has two and a half fold increase in cigarette smoking and marijuana. Looking at the health costs, this is one of my last slides and it shows here. So it's looking at associated health care expenditure from the year 2000 through the year 2009. The first data here is from the neonatal abstinence syndrome and the data down here is all other U.S. birth. Look at the numbers. First, they are increasing over the 10-year study from 39 up to 53,000. So it is really increasing. And looking at also comparing the NAS expenditure for NAS versus all other group together or other birth, you could see a striking difference from 47, nearly 48,000 to 7,000. Same thing with Medicaid and over the years, expenses are increasing. The Maryland Patient Safety Center has an abstinence collaborative, NAS collaborative. It's been there for a while but it kicked off in October 2016. We are part of this collaborative. Our goal is to decrease the length of stay for NAS admissions and to try to standardize the scoring and the treatment. We don't have a lot of read admissions. I'm not sure if because we don't or because they go to the community and we don't see them. So now we are using the CRISP to look up this data. On the VON website, there are 18 micromodules or lessons and they are excellent and they are worth actually going through. And they are also ABP approved for credit for MOCs. So frontiers and interventions, I would say if I could prevent the wind-up in the full-term nursery, I don't know how to do this. And you're thinking of having our cutlers go to full-term nursery before the wind-up starts. Decreasing the inter-rater variability in the scoring system, maybe using of a weight-based medication. I personally do not think it makes a difference. But I think individualized and PRN, pharmacological medications, is the future. Developing an NAS-baby's focus cutler program, and we are developing this as well. Maternal support, avoiding blame, promoting breastfeeding, treatment of NAS-impostnatal words, mother's rooms. Again, depends on resources and culture. And then the last thing and it's the future, is the fetal and neonatal genetic blueprinting. Again, I'm not sure this will change the duration of treatment. It will just give you more information about the babies and we have to weigh this against expenses. I would like to acknowledge my team, my research fellows, Ahal Azim Abinov-Parek, who is working now on the genetic implications and the SNP arrays for our babies. Our data manager Kelly, that helped in the 10 years data. Our two nurse practitioners working in NAS, our cost analysis from the hospital. Also the NAS quality improvement project team.