Are peripartum opioids safe for breastfeeding mothers?

Welcome back to Depth of Anesthesia. This is a podcast where we critically explore our own. Clinical practices. I'm David Hao and I'm an anesthesiologist at the Massachusetts General Hospital. Our first guest today is Dr. Gopika Hari, an anesthesia resident at the MGH.

And she's a graduate of the Washington University School of Medicine in St. Louis. Welcome to the show. Thank you, Dr. Howe. Excited to join you here today. It's a pleasure to have you and I appreciate you reaching out to me to to get this recorded because I know a lot of the work that we had done was it was almost a year ago now.

Our second guest today is Dr. Lana Jude. Dr. Jude is a graduate of the Anesthesia Residency here at MGH, and she's currently a faculty member. The responsibilities on multiple services, including the obstetric anesthesia service. Lana, welcome to the show. Thanks, David.

It's a pleasure to be here. Our case today involves a 32-year-old woman. Who undergoes a C-section to deliver a healthy full-term baby boy under spinal anesthesia? Due to significant pelvic adhesions, the surgery takes a bit longer than anticipated And during the last third of the procedure, the patient starts to experience some increasing pain and pressure, which prompts the team to administer IV fentanyl and morphine for pain control. And post -operatively, she reports ongoing pain at the incision site.

The resident who is caring for this patient expresses some hesitation about offering additional opioids. specifically citing concerns about potential effects on the newborn, since the mother told this resident that she plans to breastfeed. Dr. Hari, what are some of the claims in this case? Thank you for this case, Dr. Howe. The core claim we're examining today is this. Breastfeeding mothers who receive opioids perioperatively should, quote, pump and dump their breast milk to protect their newborns from potential harm.

So here now are two questions for our listeners to think about. What's the level of your agreement with the claim that breastfeeding mothers who receive perioperative opioids should, quote, pump and dump And what is the level of evidence for what you believe? Dr. Hari, I know we worked on this topic as part of the Depth of Anesthesia Elective, and I'm curious what got you interested in this topic in the first place. I think I've always been interested in maternal and peripartum health. Um, and especially after doing an OB anesthesia rotation, I feel like the labor process is a very stressful But pivotal moment for a lot of patients, and I think a lot of new moms just want to do what is most safe for their babies.

I found this topic interesting because it highlights the balance Between providing adequate pain control for mothers and ensuring an optimal safety profile for the neonates. Breastfeeding offers really important health benefits to infants, including enhanced immunity and cognitive development. And that first breast milk expressed after labor, the colostrum, is especially rich in these primary immunoglobulins and growth factors that support neonatal development. Thanks to interdisciplinary collaboration amongst OB, anesthesiology, and pediatrics, critical analyses of available data has helped to dispel a lot of the misconceptions about breastfeeding in the context of anesthesia and I think it would be interesting to really explore it some of the medications we use in particular. I definitely appreciate that sentiment.

And I I think one area worth exploring or getting us started here is what the current guidelines say about the safety of various anesthetic agents. in breastfeeding mothers. And then more specifically, are there recommendations out there when it comes to opioids themselves Absolutely. The American Society of Anesthesiologists released guidelines in 2019 advising against the practice of pumping and dumping breast smoke after anesthesia. While all anesthetic and analgesic medications do transfer into breast milk to some degree, the ASA emphasized that these concentrations are typically very low and even lower in neonatal circulation. making them clinically insignificant in most cases. The Association of Anesthetists published similar guidance in 2020, encouraging mothers to resume Breastfeeding as soon as they're awake, alert, and able without the need to discard any breast milk.

Both sets of guidelines affirm the safety Of a broad range of medications during breastfeeding, including local and regional anesthetics such as the agents we use in our epidurals, IV induction drugs such as propofol, thiopentol, and automatic volatile anesthetics, neuromuscular blockers, and non-opioid analgesics. Where there is a little bit more nuance is with opioids. As we mentioned earlier, both societies emphasize the value of local and regional techniques to minimize systemic opioid use. They also support the use of non-opioid analgesics such as acetaminophin and NCEDs, where they're IV or oral for postoperative incisional pain, as these are safe during breastfeeding. ACOG released similar guidelines supporting first use of acetamedethin and NSAIDs and then opioids as needed.

So building on that, I think we do want to zoom in on opioids most commonly used in the perioperative context. So these are drugs like morphine, oxycodone, hydromorphone, fentanyl, uh, and even remifentanil. Before we start to dive into each one individually, I think it's probably helpful for us to step back a bit and ask, are there any overarching pharmacokinetic principles that actually help us predict how much of a given opioid actually reaches the breastfeeding infant. Definitely. Expert opinion from Illit and Christensen back in 2005, along with work by Edo and colleagues in 2000.

Introduce this concept of a relative infant dose or RID. This is expressed as a percentage calculated by dividing the infant's estimated daily dose from breast milk by the maternal daily dose consumed. As a general rule, an RID of 10% or less is considered an acceptable threshold for drug exposure through breastfeeding for a variety of different drugs That said, RID is just one piece of the puzzle. A number of additional factors influence actual drug exposure in the infant. For instance, some studies use predicted or calculated milk to plasma ratios rather than direct measurements, and the timing of sampling, especially in relation to steady state, can vary significantly.

It's also important to consider that a single dose may behave very differently from repeated or cumulative dosing. Neonatal drug clearance is immature and variable and first pass metabolism after oral ingestion through breast milk can significantly reduce the systemic impact of some opioids. So while the RAD provides a helpful framework, it doesn't fully capture the complexity of drug transfer and its effect in the breastfeeding infant. That's a great point. And I'd also add that while pharmacokinetic models like RID are incredibly useful, they don't tell the whole story.

In real-world practice, the subjective signs in the infant can be just as important in assessing potential drug effects. And given the wide variability in neonatal physiology, especially in premature or medically complex infants, a one size fits all threshold doesn't always apply. On top of that, breast milk concentrations themselves can vary quite a bit, not just between patients, but even within the same mother. The amount of drug expressed in breast milk can fluctuate based on factors like timing relative to dosing, for milk versus hind milk composition, and even maternal metabolism, none of which are easy to standardize in a clinical setting. So while RID and similar quantitative tools are valuable guideposts, especially when we're dealing with drugs that have either very low or clearly concerning RID values, We always have to interpret them in the broader clinical context.

At the end of the day, it's about balancing the data with close observation of the infant and a thoughtful approach to maternal care. Absolutely. And I I think that is a key perspective to keep in mind as we start to dive into the evidence. Pharmacokinetic data can be helpful. Particularly when we're evaluating early studies or maybe newer drugs.

But in preparing for this case with Dr. Hari, I think one thing that stood out right away was just how limited sometimes the evidence base was here. There are very few large studies and even fewer randomized trials focused specifically on opioid use in breastfeeding patients. That's maybe not surprising given the clinical and maybe ethical complexities involved, but most of the data that we ultimately do have comes from small single-center observational studies and often with somewhat limited follow-up. So as we explore the five opioids we'll be focusing on today, morphine, oxycodone, hydromorphone, fentanyl, and remifentanil. We're going to do our best to highlight the most impactful and clinically relevant studies in this space.

So let's jump into our first drug, morphine. One of the earlier studies that looked at morphine transfer into breast milk was a 2002 paper by Baca and colleagues from a single center in France They followed seven breastfeeding mothers who received either IVPCA morphine after cesarean delivery or intrathecal morphine This was a descriptive study that measured both morphine and its active metabolite, M6G, in maternal plasma and colostrum at multiple time points over 48 hours. On average, women received about 0.58 mg per kilogram of morphine in the first 24 hours, tapering to 0.17 mg per kilogram in the second 24 hours What's interesting is that only three of the seven mothers had measurable levels of morphine and M6G in their colossum et al. Importantly, even at the highest measured concentrations, The estimated drug transfer to the infant was minimal, roughly 0.005 mg of morphine and 0.1 milligrams of M6G per 100 milliliters of milk So the takeaway here is that for moms using a morphine PCA post-caesarean, the concentrations of morphine and its metabolite in colostrum appear to be quite low and likely clinically insignificant for the breastfeeding infant.

Yeah, absolutely. This study offers a few important insights. It directly measured both morphine and M6G concentrations in colostrum over 48 hours which is especially valuable given how little data we have on early postpartum milk. And including M6G is key. It's a more potent metabolite and potentially more relevant for neonatal effects.

Interestingly, only 3 out of 7 mothers had detectable drug levels in colostrum, which really highlights how variable this can be. I think it would have been helpful to see neonatal plasma levels or behavioral data for those infants to better link drug levels with clinical outcomes For context, a 3-kilogram infant would need around 150 to 300 micrograms of IV morphine for a therapeutic dose. Based on the study's findings, it's highly unlikely a newborn would ingest anywhere near that amount from breast milk in the first day. And that doesn't even account for the 50% reduction from first-pass metabolism. As for M6G, the study found higher concentrations in milk than in plasma, and higher than morphine itself.

But again, the absolute values were small, and with only 20 to 30 percent or bioavailability The clinical relevance appears minimal. Yeah, and I think your perspectives underscore two key points for me. First, even with direct measurement, it seems like there's a fair amount of variability in colostrum levels, and the absolute drug amounts still seem fairly low, especially when you factor in limited neonatal intake and reduced oral bioavailability. But second and maybe more importantly, we are still left wondering about the clinical effects. As you mentioned, Lana, it's one thing to measure trace concentrations in milk, but what we really care about is does the baby show any signs of sedation?

Feeding difficulty, alter neurological function. And that question brings us to the next study, which actually shifts focus from pharmacokinetics to behavior. Whittles and colleagues took a different approach by looking at neonatal neurobehavioral outcomes after maternal exposure to both epidural morphine and IVPCA morphine. This was a prospective study out of the University of Chicago by Whittles and colleagues looking at whether different maternal, post-caesarean analgesia regimens impacted neonatal behavior. They enrolled 98 neonates, 47 breastfed infants whose mothers received epidural anesthesia with morphine, and they were randomized to either PCA morphine or PCA meparidine, and then fifty-six bottle fed infants as a control group.

Importantly, the decision to breastfeed was made by the mothers, and only those who chose to breastfeed were randomized. They used the Brazalton Neonatal Behavioral Assessment Scale, or the NBAS. to evaluate neurobehavioral outcomes over the first four days of life by assessing autonomic regulation, motor development, state regulation, and social engagement. They also assessed different standard metrics such as APCAR scores and respiratory rates. In the first two days, there were no significant differences across the three groups in any of the measured outcomes. But by day three, infants in the morphine PCA group were significantly more alert and responsive to human cues compared to both the Myperidine group and the bottle-fed controls.

That trend held on for day four as well. Those in the morphine group continued to score better on orientation to auditory human cues than those in the Meparidine group. I found the results of that study to be particularly interesting. While this wasn't a full randomized control trial, it's one of the few prospective studies in this space that included a randomization component. and the results are actually pretty reassuring when it comes to morphine. Not only did the morphine group perform better than the Maparine group, but by post operative day three they even showed improved or equivalent neurobehavioral outcomes compared to the bottle fed control group.

That said, it is worth noting that the authors partially attributed those improved scores to increased maternal-infant interaction in the breastfeeding group. So I'd be cautious about interpreting these findings as purely drug-related. Still, the fact that no behavioral um impact was observed negatively is clinically meaningful. So if we apply that to clinical practice for patients receiving very short courses of opioids, then their risk of cumulative opioid transfer through breast milk is likely quite negligible. So I think taken all together, obviously acknowledging the limitations of these studies, we are at least getting the sense that Morphine seems like a relatively safe option for breastfeeding mothers in the immediate postpartum period, especially when used within the typical perioperative doses.

As we mentioned at the top of the show, of course, morphine isn't the only opioid in play, and oxycodone has become increasingly common for postpartum analgesia, both in inpatient and outpatient settings. But unlike morphine, the date on oxycodone and breastfeeding safety has probably raised a bit more concerns. And one of the more widely cited studies in this space comes from Lam and colleagues in 2012, which Dr. Hari is going to walk us through next. Thank you, Dr. Howe. This 2022 study by Lamb and colleagues took a different approach.

It was a retrospective cohort analysis based on calls made to the Mother Risk Program in Toronto Which provides evidence-based counseling on medication safety during pregnancy and breastfeeding. Out of over 1,500 women who contacted the program between 2004 and 2008, The researchers identified 533 mother-infant dyads that met inclusion criteria and completed follow-up interviews. These were then divided into three groups, 139 who had used oxycodone, 210 who used codeine, and 184 who took only acetaminophen. The primary outcome was maternal report of neonatal central nervous system depression, things like excessive sleepiness, poor feeding, or low responsiveness What stood out was that 20% of mothers in the oxycodone group reported signals of neonatal CNS depression, compared to just 0.5% in the cetametaphen only group.

That's a pretty striking difference with an odds ratio of 46. About 17% of mothers in the codeine group reported similar symptoms, but this wasn't statistically different from the oxycodone group Interestingly, higher maternal oxycodone doses were associated with symptomatic infants. Still, none of the women exceeded the commonly accepted maximum of 40 mg a day Four infants were also reported to have irregular breathing, and while these were self-reported outcomes, 38 of the 39 mothers noted that the symptoms resolved once the oxycodone or breastfeeding was stopped Thank you for referencing this study, Dr. Hari, because this is often quoted when we talk about caution around oxycodone use during breastfeeding, and for good reason. After concerns emerged about codeine, particularly following a tragic case report of neonatal death linked to ultra-rapid CYP2D6 metabolism and then accumulation of toxic metabolites.

Oxycodone started being used more frequently as an alternative. But given the oxycodone is also partially metabolized through the CYP2D6 , There were reasonable concerns about whether it might pose similar risks, especially in the breastfeeding infant. Given its sample size, the study by by Lamet et al. is one of the most frequently cited in the discussions about opioid safety during during lactation. But it is worth pointing out a key distinction. The data were collected from mothers who reached out to the mother risk program, often weeks to months postpartum.

That's a bit different from the immediate perioperative window we typically focus on, those first 24 to 72 hours after delivery. Still, the findings that higher maternal doses were associated with increased reports of neonatal sedation is relevant, even in the short term, especially if dosing is repeated or prolonged. There are a few major limitations to keep in mind. The study likely included a population of mothers who were especially vigilant, since they proactively called a medication safety line. That could lead to an overestimation of adverse events, and the authors acknowledged the potential for recall bias.

And while they did note serious adverse events like ER visits in the coding group, No such outcomes were reported for oxycodone. So the concern here is more about mild to moderate CNS depression that's reported by the mothers, rather than life-threatening toxicity. And to your point, Dr. Judet, I think there needs to be conversation about the limitations in this study. Because a study in which adverse events are recorded by participants self-reporting is going to be subject to recall bias where participants might forget, misremember, under-report. Reporting bias where you might selectively report symptoms based on your expectations or beliefs.

And also there's a lack of ultimately clinical verification and it's hard to objectively validate some of these reported symptoms. So all those things do need to be considered carefully in the context of interpreting this data. So to then move us from reported symptoms to measurable exposure with oxycodone, our next study takes a more pharmacokinetic lens. Seton and colleagues set out to determine just how much oxycodone actually makes it from mother to infant by looking at things like maternal plasma. breast milk, and critically neonatal plasma levels after cesarean section. This two thousand seven study by Seton and colleagues is one of the few to directly measure neonatal plasma levels of oxycodone alongside maternal plasma and breast milk concentrations.

They followed 50 breastfeeding mothers who were receiving oxycodone after cesarean section as part of a multimodal analgesic regimen The mothers received a 30 mg rectal dose at the end of the case, followed by a 10 mg oral dose every two hours as needed, with a maximum daily dose of 90 mg. Samples of maternal blood and breast smoke were collected at 24, 48, and 72 hours, and neonates had their blood drawn at 48 and 72 hours to assess plasma oxycodone levels. They also used a 1 to 5 numerical scale to assess neonatal sedation and breast attachment. In terms of breast small concentrations, the mean levels were highest in the first 24 hours and gradually declining by 72 hours.

However, oxycodone was still detectable in breast milk up to 37 hours after the last maternal dose in about 10% of the mothers. As for the neonates, in all but one case, oxycodone levels were undetectable. The one infant who had measurable levels showed 7.4 nanograms per milliliter. and 6.6 nanograms per milliliter on retesting, still far below the concerning threshold. Neonatal sedation scores were generally low. with fewer than four percent of infants scoring a three on the sedation scale at forty eight hours, and none scoring in the four to five range. The study found no clear correlation between maternal dose, breast milk levels, and neonatal sedation So really the big takeaway here is that at a typical post-caesarean dose, oxycodone appears to result in minimal transfer into neonatal circulation, with no evidence of clinically significant sedation or toxicity in the first 72 hours.

One detail that stood out to me was the one neonate with a measured plasma oxycodone level of 7.4 nanograms per ml, which the authors note is likely within the therapeutic range for a two-day-old infant. The study estimates that a three kilogram neonate would need to consume about three hundred mL of breast milk containing a hundred nanograms per ml of oxycodone to reach a therapeutic dose, something that's pretty unlikely in the first forty eight hours of life. That said, the authors are transparent about the limitations of the study. Not all mothers reach steady state, and many of the milk and plasma samples We're not taken at peak plasma times, which for oxycodon is around one and a half to two hours post dose.

So there's a chance that higher transact concentrations could have been missed But overall, the study makes a strong case for balance. They write, the benefits of providing effective analgesia for maternal comfort and successful initiation of breastfeeding would appear to outweigh the risk of oxycodone exposure in the breastfeeding infant during this period. End quote. Still, they emphasize the importance of monitoring for signs of opioid exposure. things such as sedation, pore latching, GI symptoms, or respiratory depression. So while it's not a complete green light for unrestricted use, The study adds some nuance.

It suggests that when used appropriately in the immediate postpartum period, short-term oxycodone likely carries low risk, but clinical vigilance is always key I definitely appreciate that perspective, and I think you did a really nice job of contextualizing these findings within the broader conversation as it pertains to oxycodone. And I think that brings us now to hydromorphone. And most of what we know comes from a very small pharmacokinetic study by Edwards and colleagues back in 2003, which Dr. Hari will walk us through next. Yeah, this 2003 study by Edwards and colleagues is really one of the only dedicated pharmacokinetic investigations we have on hydromorphone transfer into breast milk. It was a small study, just eight healthy, non-smoking lactating women at the University of Kentucky who received a single 2 mg intranasal dose of hydromorphone.

The aim was to characterize how the drug distributes into milk and estimate infant exposure. They used liquid chromatography to analyze both maternal plasma and breast milk samples. And one interesting finding was that the hydromorphone distributes rapidly into milk but doesn't partition into fat. The whole to skim milk ratio was about 0.98. That suggests that fat content isn't a major factor in hydromorphone transfer, which is somewhat different from more lipophilic opioids.

Milk concentrations peaked around two hours after administration, with a half-life of elimination from milk of about 10.5 hours. They estimate that a breastfed infant would ingest roughly 0.67% of the maternal dose adjusted for body weight For context, the therapeutic neonatal dose is about 0.03 mg per kilogram orally every 3 to 4 hours, so the amount received through breast smoke would be significantly below that. The bottom line, in the setting of a single dose exposure, the amount of hydromorphone transferred to a breastfeeding infant seems pretty low That said, some of the exposure estimates are based on theoretical calculations rather than direct measurements of neonatal plasma, which limits how confidently we can generalize these findings, especially for repeated or higher dose scenarios.

Yeah, and so I think a reasonable takeaway is that the available data at least suggests that there is minimal transfer after a single dose. But as Dr. Hari pointed out, these rely on modeled estimates rather than measured infant levels. And we still don't have much data on repeated dosing. So We're fairly limited in how broadly we can apply these findings, especially in real-world settings where it's not uncommon for patients to receive multiple doses over time. So that brings us now to fentanyl, which is widely used through labor, often via epidural or iV routes.

And It does have a very different pharmacologic profile compared to the other opioids we've discussed thus far. And the next study by Ummen and colleagues looks at a different kind of endpoint. Not drug levels, but how intrapartum fentanyl exposure may impact early breastfeeding behavior Yeah, this 2021 Prospective observational study by Umman and colleagues looked at how intrapartum fentanyl exposure, both IV and epidural, affects early breastfeeding behaviors. It included over 1,100 healthy mothers of term singleton infants at Sortland Hospital in Norway. Mothers self-selected their analgesia, falling into one of four groups, no opioids, ivifentanyl only, epidural fentanyl only, or a combination of both.

The ivifentyl group was further stratified by dose 0 to 200 micrograms and 200 to 500 micrograms. The study found a clear association between fentanyl use and early breastfeeding challenges. Compared to mothers who received no opioids, the odds of non-exclusive breastfeeding at hospital discharge increased with opioid exposure nearly doubled with IV fentanyl alone, more than doubled with epidural fentanyl, and quadrupled when both RATs were used. Spontaneous suckling behaviors were also significantly reduced across all fentanyl groups, regardless of administration route. Doses mattered too.

When iVentanyl exceeded 200 micrograms, exclusive breastfeeding rates dropped from 89 to 81%, and spontaneous suckling from 83 to 68% Breastfeeding difficulties were more commonly reported in the higher dose groups as well. Since fentanyl is a widely utilized medication in the peripartin period, the study addresses a relevant and practical issue in obstetrics. The study, however, in my view, has a few important limitations. The primary outcome is non-exclusive breastfeeding at discharge Which depending of the timing of the discharge, which for a multiperse woman the average was 2.2 days, and for a nolop was 2.9 days. So this may or may not be related to the effect of fentanyl, given the short half-life of this medication.

As a prospective observational study, we cannot currently establish causality from it But at minimum it does give a reassuring signal that at doses of less than 200 micrograms, fentanyl is less likely to have an effect on breastfeeding behavior However, there may be multiple confounding factors not accounted for, such as maternal health, labor complications, and duration, or availability of breastfeeding support that may have influenced the result of this study. So I think taken all together this study does highlight an important signal, which is perhaps that higher doses of fentanyl might have some interference with early breastfeeding behaviors. But of course the devil is in the details and there's a lot of nuances to this study that require a little bit more interpretation to actually draw firm conclusions from.

To get at some potential explanations for the signal that we're seeing in this study, the next study takes a little bit of a different approach. It's a prospective randomized double-blind trial that directly measured fentanyl concentrations in colostrum and examined neonatal feeding behaviors following cesarean delivery. This 2008 study by Goma and colleagues offers one of the few randomized double-blind trials looking at fentanyl transfer into colostrum and its impacts on early neonatal feeding behavior. It enrolled a hundred healthy breastfeeding mothers undergoing cesarean delivery at Cairo University, all of whom had breastfed in previous pregnancies They were randomized to either receive epidural fentanyl with an N of 50, or IV fentanyl as part of spinal anesthesia, also with an N of 50.

All infants had reassuring APGAR scores and required no resuscitation. The team assessed newborn feeding behavior using the Preterm Infant Breastfeeding Behavioral Scale, or the PIBBS, at 24 hours. They also collected colostrum samples at 45 minutes and again at 24 hours to measure fentanyl concentrations. Interestingly, while there was a statistical difference in PIBBS scores between the groups, epidural groups scoring slightly higher than the IV group, with a mean of thirty five versus thirty four, the authors noted that it was unlikely to be clinically meaningful. Fentanyl concentrations in colostrum were higher in the epidural group at both 45 minutes and again at 24 hours, but these levels were quite low overall.

There were no differences in supplemental bottle feeding or other clinical outcomes between the two groups. So the takeaway is that fentanyl, whether given epidurally or intravenously, appears to result in only minimal colostrum transfer and does not seem to meaningfully impact early breastfeeding behavior in healthy term newborns. I think the study does a nice job of showing that while there were statistically significant differences in breastfeeding behavior scores Between epidural and ivifentanyl groups, the differences are likely not clinically meaningful. For context, the PIBBS scale has a maximum score of 42. And scores under 20 are generally considered indicative of immature breastfeeding behavior.

Both groups in this study were well above that threshold, a median score of 34 and 35. So we're really looking at a small numerical difference without any obvious functional impact. The authors themselves make this point and reference a a cohort study by Chang and He-Man. which also found no difference in infant neurobehavioral outcomes at 24 hours between IV and epidural fentanyl. So the study supports that existing body of evidence. A strength that we have here is that it's a prospective randomized double blind trial, something that we frankly rarely see in this space.

It directly compares two common modalities of fentanyl administration and looks at infant behavior in the first twenty-four hours. without reporting any adverse signs of sedation in either group. As for limitations, colostrum levels were only measured at 45 minutes and 24 hours, so we don't know whether those time points captured the true peak concentration. But even on a worst case exposure, the authors did the math for this and uh they suggested even if colosterum levels reached one nanogram per ml and an UNA ingested 100 ml, which is on the high side the total fentanyl dose would be around 0.016 micrograms per kilogram. This is assuming 49% oral bioavailability To keep it simple, that's well below any dose expected to cause harm in a healthy newborn.

So all in all, this study offers reassuring evidence that both IV and epidural fentanyl, when used for cesarean delivery, results in minimal neonatal exposure. and do not appear to negatively impact early breastfeeding behaviors. I think that was a really comprehensive take on that paper. And I think you carefully pointed out some of the key considerations. that allow us to ultimately interpret that data. So let's move on now to our final opioid in question, Remifentanil. This is a super interesting case because of its unique pharmacokinetics.

And as many of you know, it has a rapid onset and an extremely short latency to peak effect. And what really sets it apart is its ultra short half life. And that rapid breakdown in half life does raise an interesting question, would Remyfennel even have time to transfer into breast milk in a meaningful way? As a quick aside, we actually explored the idea of implementing a Remy Fentanyl-based labor annual zesia protocol at our own institution. uh given some of these potential theoretical advantages, especially for patients who can't or prefer not to have neuroximal anesthesia. Uh but ultimately we're it wasn't put into practice locally because of some concerns around safety, staffing, and monitoring logistics.

But I thought that was just an interesting tidbit. Dr. Hari is now going to take us through the data that we do have in the Remifentanil space. This twenty fourteen study by Stockey and colleagues is one of the few randomized controlled trials to look at remifentanil in the labor setting particularly its effects on both maternal and neonatal outcomes. It was a single-centered non-blinded non-inferiority trial that randomized 44 laboring women to either IV patient-controlled Remifentanil or epidural PCEA with bupacaine and fentanyl. Crossover was allowed after 30 minutes and the study was analyzed by intention to treat.

In the end, 19 women remained in the remifentanil group with three crossing over, and 20 were in the epidural group with one crossover. From a maternal perspective, Remy fentanyl was associated with worse pain control and lower respiratory rates. But when it comes to neonatal outcomes, specifically respiratory rate and APGAR scores, which were secondary endpoints, there was no significant difference between the two groups. There were two neonates in the Remy fentanyl group who required some initial resuscitation. One received stimulation and supplemental oxygen, and the other required stimulation and brief bag mass ventilation for about thirty seconds.

Their APAR scores at one minute were seven and six, improving to eight and ten at five minutes. No neonates in the epidural group required any resuscitative intervention, but the difference wasn't statistically significant Overall, the average neonatal respiratory rates and apgars were similar between groups. Respiratory rates of 48 and 49 breaths per minute and median apgars of 9 and 10 at 1 and 5 minutes, respectively. No neonatal adverse events were reported in the postpartum period in either group. So, in terms of immediate neonatal outcomes, IV Remy fentanyl appears to not increase the risk of respiratory depression or adverse if Fex compared to epidural anesthesia.

Though larger studies would be needed to confirm these findings with more statistical power Mm-hmm. Absolutely. And one thing to highlight here is that while two babies in the Remifentanil group did require some form of resuscitation, it's not entirely clear that the Remifentanil was the cause, especially considering its extremely short half life. any direct fetal exposure would have likely worn off very quickly after delivery, and by the time breast milk is being produced and expressed, it's reasonable to question whether any remifentanol would remain in colostrum at all. That's part of what makes Remifentanil such an interesting candidate. For mothers who are particularly concerned about opioid transfer through breast milk, Remifentanil could theoretically offer effective labor analgesia. with minimal or even negligible exposure to the neonatia lactation.

But the key word here is theoretically, we still don't have data measuring rhomifhenyl concentrations in colostrum. So while this study is reassuring in terms of immediate neonatal outcomes, we'd really benefit from follow-up studies that directly assess milk concentration and neonatal exposure after maternal use. So all in all with Remifentanil, it does seem like the pharmacology is promising. And at least within the data that we do have, there's an indication of perhaps minimal neonatal impact. But as Dr. Jude said, we are still waiting on more definitive studies, especially around breast milk transfer.

So that wraps up our review of the five opioids that are most commonly used in the perioperative and peripartum space. And Dr. Hari, after walking us through a lot of this literature from the pharmacokinetics to behavioral outcomes, what are some of your big picture takeaways for clinical practice? Absolutely. It was really great to look at both the guidelines and the nuances of some of these studies throughout this podcast. Across the board We see that short-term perioperative use of common opioids like morphine, oxycodone, hydromorphone, fentanyl, and even remifentanil result in relatively low doses of drug transfer into breast milk.

And when we look at studies that go one step further, examining neonatal plasma levels, feeding behaviors, and early neurodevelopmental outcomes, we generally don't find evidence of clinically significant harm. That said, there's nuance. Morphine has the most robust and reassuring data. Oxycodone, while more commonly associated with reported neonatal sedation, appear safe at standard post-caesarean doses when used briefly and with close monitoring. Hydromorphone data is limited, but studies suggest very low milk transfer after single doses Fentanyl shows minimal impact on neonatal feeding behaviors when used for C-section, though higher doses during labor may influence early latch and breastfeeding success.

And Remifentanil, thanks to its ultra-rapid metabolism, likely poses negligible lactational risk, though we're still lacking direct milk concentration data. Wonderful, Dr. Hari, thank you so much. And here now again are two questions for our listeners to reconsider. What is the level of your agreement with the claim that breastfeeding mothers who receive perioperative opioids should, quote, pump and dump? And what is the level of evidence for what you believe?

Dr. Hari, thank you so much for all your efforts in putting together this podcast. I appreciate it immensely. Thank you. It was great to be on this podcast. And Dr. Jude, it's a pleasure as always.

I appreciate all of your input and key expert insights. Thank you so much. It was a pleasure to be on here and discuss the the evidence behind our clinical practice.