WSC Spotlight – Maternal Sepsis

Good morning, good afternoon, or good evening, depending on where you are in the world There are 7,000 of you, in fact, more than 7,000 of you from over 100 countries And a very warm welcome to all of you to the second session of the World Sepsis Congress Spotlight on Maternal and Neonatal Sepsis We had an excellent first session on some of the key challenges relating to maternal and neonatal sepsis In this session, we will shine a spotlight on maternal sepsis, the third commonest killer of mothers We have five very eminent speakers who will cover a range of subjects Starting with such fundamentals as the definition of sepsis to prevention and management of sepsis You will also hear about some really exciting new research work that aims to address maternal sepsis comprehensively Each speaker has about 15 minutes, and I hope there will be time for some questions at the end of each talk, and some time at the end of the session for questions and discussions So let’s get started The first talk is on the challenges, burden, definition, and identification of maternal sepsis And this will be given by Joao Paulo, Professor Paulo So Joao Paulo trained as an obstetrician and gynecologist with a specialization in intensive care medicine, with extensive experience in global health Joao Paulo worked also as a professor of social medicine at the University of Sao Paulo Joao Paulo is based at the Department of Reproductive Health and Research at the World Health Organization Over to you Joao Paulo Greetings from Geneva Thank you, Arri, and thank you for the participants for your audience I’m glad to talk to you today about the challenges, the burden and the definition and identification of maternal sepsis And this is starting with the burden I need to remember you all that every year there’s an estimated number of 303,000 maternal deaths taking place around the world About 25% or more of these deaths are related to maternal sepsis And I want to use some of my time to explore a little bit the burden So we have about 11% of all maternal deaths that the underlying cause is infection and/or sepsis And that’s represented about 35,000 maternal deaths every year that are initiated by an infectious condition that evolves into sepsis But we have an estimate that can reach up to 100,000 maternal deaths in total, where other causes they appear as the underlying condition and they evolve into sepsis and then a maternal death So here I have an example For instance, there’s a woman that develops a postpartum hemorrhage, then evolves into hypovolemic shock She receives adequate resuscitation but still develops a bacterial translocation and then days later, sepsis and eventually, this woman will die of sepsis

We could think of different examples relate to hypotension for instance where the primary cause is a hypotensive disorder that evolves into a complication, for instance, a stroke for example, and then a asperative pneumonia, sepsis and then death So the total burden of sepsis related to pregnancy is estimated around 100,000 maternal deaths every year And there are some important challenges that need to be addressed if we want to tackle this burden if we want to alleviate this burden The first one is that sepsis as you know, it’s a very heterogeneous condition Different signs and symptoms can be associated with sepsis Sepsis during pregnancy and among young adults, which is frequently the case among pregnant women can be difficult to recognize and when it becomes evident, sepsis in that population may be already in severe and then advanced with a reduced chance of survival So it’s very important for us to develop ways and our knowledge and our technology to be able to identify sepsis as soon as it’s possible As soon it can be feasible its identification We have also an update in terms of definition If you recall from the previous session that this has been already mentioned and we will go back to this issue, in that 2016, there is a new sepsis definition that has been proposed for the general population by the 3rd International consensus on Sepsis and Septic Shock In this new definition, the importance of systemic inflammation has been reduced and there is an increased focus on organ dysfunction So in a way, we’re talking now in terms of identifying sepsis, it’s an infection that evolves with an organ dysfunction, or if you prefer an organ dysfunction that develops in the patient with infection Based on this new definition we need to consider that pregnancy was not part of the works or it was not considered in that when the Sepsis 3 consensus was prepared So the maternal physiological changes during pregnancy and the postpartum period, they make the diagnosis of sepsis more complicated and obviously, this can have an impact in the way we’re going identify sepsis cases And from the other side, there are different definitions and concepts that are related to maternal sepsis currently in use when we think of obstetrics, or midwifery and maternal health We are familiar with endometriosis, we’re familiar with puerperal sepsis, abortions for instance, so the different conditions that are related to sepsis but so far there was not one single unifying definition that is also up to date with the current understanding of sepsis in general So the WHO started then to develop a definition on maternal sepsis and here, you’re seeing the results of a systematic review and an expert consultation All the published literature and WHO documents were reviewed There was a multidisciplinary international panel of experts that was consulted through online surveys and in-person meetings, and the definition that was product of this process is, Maternal sepsis is a life-threatening condition defined as organ dysfunction resulting from infection during pregnancy, childbirth, post-partum, or post-abortion period

So that is the definition that has been proposed by WHO in 2016 as a result of an extensive systematic review and consultation process in order to get it aligned with the new definition There is also a statement on maternal sepsis that recognized the need to foster new thinking and catalyze greater action to address this important cause of maternal mortality And the idea is that the definition where we put infection plus organ dysfunction result in maternal sepsis is also an actionable definition So the importance of early recognition of the condition, immediate use of fluids and provide hemodynamic support, antibiotics, monitoring, referral and addressing also the source We will see more of the tales of this condition as the series of presentations evolve In terms of identification, it is still, WHO is working in very clear and simple to use, practice-orientated identification criteria but I think it’s important for all of us to have very clear in our minds that whenever we have a suspected or confirmed infection, we should also look for organ dysfunction that can be in the suspicion or in a confirmation And also, whenever we have abnormal vital signs or laboratory exams, and whenever we see a patient, a pregnant woman that’s not looking very well – looks unwell – we should really think of sepsis So sepsis can be a hidden cause that is motivating some atypical conditions and manifestations of organ dysfunction even when we don’t have infection very clearly presented To address this, WHO and a number of other organizations have started a Global Maternal and Neonatal Sepsis Initiative that is actually organizing this event, this event fantastic World Sepsis Congress Spotlight So we have different organizations, particularly the Global Sepsis Alliance And in order to finish my presentation, there’s a take-home message I want to reemphasize the importance of sepsis as one of the main causes of maternal deaths There is a new definition of maternal sepsis, the concept is an infection plus organ dysfunction during pregnancy, childbirth, postpartum, post-abortion This very important message that you see repeated, now and again, to stop sepsis we need to think sepsis, and that the Global Maternal Neonatal Sepsis Initiative is a collaboration that is from different organizations to accelerate a reduction of preventable maternal and neonatal death-related sepsis With that, I would like to thank you all for your attention and I am happy to take questions and comments Thank you Great, thank you so much, Joao Paulo, for a very clear presentation I think it’s great to have a definition that we can work with and I think this will be an absolute bedrock on which we can build We have a few questions from the audience, if I may put one or two of those to you please? The first is, are there any new technologies or clinical decision support tools that you think would be useful in recognition and management of sepsis, even in the context of less developed countries? Yes, and one of the technologies that—we can think of hard technology like technology for the detection of lactate, which there are some bedside devices that are being developed and put into the market There are the possibilities of using pulse oximetry and try to develop new devices and there’s work being done to that at the low cost But I think what I want really to emphasize, the main technology that we would like to stress in this presentation and this opportunity is more of behavioral change and particularly if you start thinking of sepsis

whenever you see cases that may be atypical, that it’s not very clear, the need to think very promptly and early on sepsis And something that we would like to emphasize as well is when you systematize the approach for addressing sepsis through bundles of care, for instance, we know about bundles for developed countries but also there are new bundles in developments that are being done targeting low research settings and our next speaker will also certainly address this issue And I will leave for him the details But I want to really emphasize that’s it’s more of a cultural approach that we have to have in the organizations that is whenever we have a case of infection or atypical case of an organ dysfunction, we need to think of sepsis very promptly Great, thank you Now, this is a question relating to guidelines Are there any guidelines that people can use at the moment while WHO and partners are working up newer materials? Yes WHO has released about two years ago a guideline on maternal infection around pregnancy and childbirth and this has been published and I will post in the website of the conference the link to that So yes, there is Joao Paulo, thank you so much for the clear presentation and we very much hope that you will be able to stay on for the final discussion So we will move onto the second talk in the second session So this is on prevention and management of maternal sepsis And this talk is by David Lissauer from the University of Birmingham So Dr. David Lissauer is a clinical lecturer in maternal and fetal medicine at the University of Birmingham He divides his time between clinical work and research work His research focuses on the challenges of maternal and fetal infection, and how the maternal immune system adapts for sepsis in pregnancy So he has a combination of laboratory-based and clinical research He has worked as an obstetrician in Malawi, so he has first-hand experience and he has just recently completed the AIMS trial which investigated the prevention of infection after miscarriage surgery in Malawi, Tanzania, Uganda, and Pakistan David is also a member of the WHO technical working group on maternal sepsis and is leading the development of FAST-M, which we will hear about in a moment Over to you David Thank you very much Arri for the introduction and thank you for the invitation to talk at this fantastic congress I’m going to speak today on the prevention and management of maternal sepsis So first, really before we start, I think we should recognize that a vast majority of the burden of maternal sepsis mortality and morbidity lies of course in low-income countries and I think we need to—those of us not working there day by day need to put ourselves into a labor ward of a typical busy district hospital in sub-Saharan Africa and remember what things are like Here we have multiple women in labor taking their turn to access the labor trollies with the [jenpenji?] the pot they brought from home, midwives, and clinicians busily in attendance, moving from woman to woman, assessing them, carrying out examinations, conducting deliveries, procedures in the labor wards The equipment and resources may be scarce, need to be used sparingly The power and water, potentially is intermittent, the sink may be in the corner but is it working, is there something to dry one’s hands, is there soap there? I think if we place ourselves in that labor ward the reason for the huge burden of sepsis in this environment is clear The challenges to the patients and the practitioners working there is clear too But also the great potential as Professor Liz Molyneux said, where there’s this great potential to really improve care and outcomes So with these complex circumstances, we really need a

concerted and coordinated approach combatting the issues of infection prevention, seeking to better monitor women with infections or detect deterioration early and then, of course, improve the management of sepsis itself to reduce mortality and morbidity And that’s what I’ll briefly discuss here So before talking of the medical interventions, I think it’s critical to acknowledge the importance and the terrible state of water sanitation and hygiene in many facilities, and how this underlies the challenges of infection prevention Shockingly, one in five facilities worldwide lack appropriate toilets One in three facilities don’t have water within 500 meters and less than one in three have hand washing facilities with soap And hand hygiene isn’t just limited by infrastructure, in all settings the challenges of staffing, the time we have available as clinicians and our compliance are additional barriers But there are existing successful programs like the WHO multimodal hand hygiene approach that have shown promise to overcome these barriers and have been successfully implemented in resource-limited settings So moving on to medical interventions And these are the guidelines around infection prevention that Joao Paulo just referred to The WHO guidelines on prevention and management of maternal peripartum infections We’re very fortunate, these are excellent evidence-based guidelines published in 2015 where they took a very robust approach, engaging with a broad range of stakeholders doing 24 systematic reviews and coming up with 20 key recommendations, some of which are summarized above The crucial messages were that vaginal cleansing is recommended prior to cesarean section, though there’s uncertainty regarding the right agent to be used And other key recommendations on antibiotic prophylaxis Crucially, it shouldn’t be being given routinely for birth but should be being reserved for use prior to skin incision at cesarean section, for women having manual removal of the placenta, or for women with severe tears, where the anal sphincter has been involved or penetration to within the rectum In spite of this evidence-based guidance, it’s incomplete because there’s large evidence gaps, even surrounding common procedures and circumstances And as we’ve heard earlier in the session, the other challenge is the gap between this evidence-based practice and what has been observed being implemented on the ground And again, real opportunities here where we can improve care by devising practical ways of helping the people better implement these key recommendations So an example of our work trying to close one of these evidence gaps with the AIMS trial Despite miscarriage surgery being one of the commonest surgical procedures with pelvic infection and progression to sepsis a serious complication, there was no evidence to guide practice regarding prevention of pelvic infection and whether they should or shouldn’t receive antibiotic prophylaxis So we’ve just completed the trial randomizing 3,400 women and we’re awaiting the results But I hope that with this renewed global focus on sepsis and sepsis prevention, within maternal health, there’s going to be more opportunities to identify and close these evidence gaps to make sure that we are using antibiotics wisely and preventing infection wherever possible So moving on past infection prevention to better detection of maternal sepsis We’ve heard about the work being done on definitions

and considering the unique physiology of pregnancy to improve our detection of maternal sepsis But underlying this is what we and others have consistently observed in audits of practice, which is the observation inconsistently performed and in many facilities only done on admission or incompletely And in addition to observations, there are limitations on further investigations that can be conducted and overall a failure to recognize deterioration of mothers There are number of approaches that people are using Some are technology-based approaches like the low cost vital signs alert device, which measures blood pressure, pulse and gives a traffic light indicator based on shock index to guide people’s care being tested in the Cradle 2 trial, and other more high-tech solutions, app-based mobile approaches Our work with the Global Sepsis Alliance, the WHO, and others is on a sophisticated but low-tech solution centered around a modified early warning chart that many of you will be familiar with This is an approach widely adopted in high-income countries, it’s been adapted for a maternal population using cut offs where values have been based on existing systematic reviews of the physiological changes in pregnancy and we hope will be further adapted as more information comes from the GLOSS study that Mercedes will speak about shortly We’re currently testing the use of this chart in 16 sites in Malawi, to hopefully further adapt it and improve it But it’s been extremely well received so far The concept behind it is that practitioners are guided by the color coding of red flags indicating abnormal observation within the context of maternal infection indicate suspected sepsis and that then means that they can immediately initiate action in the form of a sepsis bundle We hope that this empowers staff to act and to act quickly to escalate or to initiate the bundle appropriately Alongside the chart, the decision tool here can guide people through that decision-making process, giving them indication of when a sepsis bundle such as the FAST-M bundle should be started or when care should be escalated In the final part of the presentation, I want to talk about maternal sepsis management itself We know from studies in non-pregnant adults in high-income countries that the use of sepsis bundles improves care and reduces mortality The bundles, by bringing together the key actions make it easy for clinicians to consistently deliver the right care to every patient in a timely way And there are excellent well-established sepsis bundles and comprehensive programs As we all know being operated in high-income countries but none of these bundles were developed specifically for the maternal context and the existing international recommendations aren’t feasible in a low-income setting In particular, our surveys of maternal health facilities demonstrates components such as blood culture and lactate very rarely available but core components of existing bundles So we’ve been working with the Global Sepsis Alliance, the World Health Organization, Jhpiego, and other partners to develop an appropriate sepsis bundle specifically for a maternal population, designed for use in a low-income country and where it can be initiated both at a health center where most women present and also in a hospital We’ve gone through a robust development process, engaging in systematic reviews, an international modified

Delphi process with 120 practitioners from more than 30 low-income countries, and then triangulated the findings with an expert panel We then went on to operationalize this through practitioner workshops and they’re currently testing it on the ground across these 16 sites in Malawi So this is an example of the treatment bundle that goes along with the training program as a physical piece of paper, an aid memoir for practitioners to use and this highlights the key components that this process develops of the FAST-M bundle So FAST-M stands for Fluids, Antibiotics, Source identification and control, Transport and Monitoring, both of mother and of the baby We really hope that with this collaborative comprehensive approach to maternal sepsis, and introducing these practical tools to help people operationalize the guidance in their own clinical practice that we can make a difference in the care they can give I’d just like to thank the many partners who are contributing towards the program and will be keen to get in contact with anyone via email or Twitter Thank you very much Thank you very much, David, it’s very exciting to hear about the development of FAST-M As you mentioned timely treatment to the right patients, which is great We have time for some questions if you would be willing to take them So the first of these, David, there is a question about the evidence for antibiotic use for termination of pregnancy, cesarean section, and episiotomy? So there is good evidence for the use of antibiotics in reducing pelvic infection at termination of pregnancy and there’s a systematic review, we ourselves conducted regarding this and there is convincing and consistent evidence that antibiotic use in that context reduces infection This is a different patient cohort and a different procedure to miscarriage surgery, and that’s really where the evidence gap existed Similarly, there’s a number of popular reviews that have examined the evidence regarding antibiotic use at caesarean section, and I think the key thing that has been brought out in the new guidance is the importance of giving antibiotics prior to skin incision and that there’s no additional benefits in giving prolonged courses of antibiotics, but a single catalyst prior to skin incision Sorry, there was a third context Episiotomy, so this is another evidence gap A simple episiotomy or for instrumental deliveries there isn’t strong evidence of benefits of antibiotic use, and in that context, it’s not currently recommended Thank you, David, a quick answer to this question, if you could please The question is, what’s the role [inaudible] so far, information to maternal sepsis? A great question and I think the answer was previously also covered by Professor Conrad Ryanheart, and the reason we took the approach of using a modified early warning score system was because we felt this encouraged a comprehensive assessment of the patient, tracking of their observations graphically over time and that this was the easiest way to integrate it into people’s routine clinical care, and this has been widely used So, [inaudible] show for itself there weren’t any women included in the cohort where it was devised and we eagerly waiting to hear if there’s more evidence of what exactly

the right thresholds and cutoffs should be for undiagnosis of suspected and confirmed sepsis Thank you very much, David David, we hope that you can stay on for the final discussion So we will move onto the third talk of the second session This is on Management of Maternal Septic Shock, and this talk will be given by Maria Fernanda Escobar Vidarte, who is a representative for Latin America at the FIGO Committee for Safe Motherhood and Newborn Health Originally from Columbia, she trained to obstetrics and gynecology and completed her clinical epidemiology masters at the University La Frontera in Chile, as well as a Fellowship in critical care and intensive care medicine at the University of Pittsburg in the United States Currently, she is a chief physician at the Obstetric ICU and Obstetric and Gynecology Service in Fundación Valle del Lili in Columbia Over to you Maria Hi. Good morning, everybody I will talk about the management of septic shock in pregnancy The objectives of this conference is to determine the definition and the main aspects of management of septic shock during pregnancy Septic shock is defined a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to substantially increase mortality The definition is according the 3rd International consensus definition of 2016 Adult patients with septic shock can be identified with a clinical consult of sepsis with persisting hypotension requiring vasopressors to maintain a mean arterial pressure of 65 mm of mercury and having a serum lactate level more than 2 mmol/L despite adequate volume resuscitation With the data hospital, mortality is in excess of 40% But this clinical definition has many different position against the war because one of the problem is related with a high specifically applicability just for hospitalized patients Now we will discuss important aspects in septic shock management In the absence of evidence-based pregnancy-specific management recommendations for septic shock, it is probably advisable to follow general management guidelines The guidelines developed by the Surviving Sepsis program can be used as a basis for the treatment of the pregnant woman with severe sepsis and septic shock Although the obstetric population was not specifically considered during the establishment of the guidelines and doesn’t have provision that consider the physiology changes during pregnancy The clinician should also assess fetal viability as resuscitation and definitive management proceed The first step in the management of sepsis in obstetric is the use of the so-called resuscitation bundle This should be accomplished as soon as possible and within the first six hours I will review a specific changes of bundles related with septic shock In the hour zero, the principal aim is to determine the severity of sepsis using a perfusion indicator In situ, it’s hypoxia, lactate is overproduced by increased analog-like qualities That the clearance cannot overcome lactic production and maybe worsened during [inaudible] status A certain lactate level more than 2 mmol/L have been used like an emerging vital sign of septic shock Lactic clearance at this time point is an important prognosis factor compared to initial zero lactate level in zero sepsis Some patients recovering from septic shock show normalized lactic levels, although vasopressors are still necessary to maintain a main arterial pressure of 65 or greater Additionally, decrease or normalized lactate levels

are important signs of recovery from septic shock This clinical findings supports the zero lactic level is a more sensitive vital sign than analog metabolizing and acidosis than blood pressure There are a few studies who are related with lactic acid in the population In the respective cohort of pregnant and postpartum patients with sign of sepsis, elevated lactic acid was associated with adverse maternal outcomes from expressing services One important conclusion was 1 mmol/L increase in serum lactate was associated with 2.34 increased odds of admission to the ICU in women with suspected sepsis either during pregnancy or postpartum period In the first hour, the effort in septic shock is a rapid use of antibiotics and avaliable resuscitation fluids in the right level and hospitalization Patients with septic shock, the rapid decompensation had been reported in those who died It has important implications for patients managed in non-tertiary centers and/or by physicians in medical ICUs not familiar with the physiological changes in pregnancy It emphasizes a need for early diagnostics and initiation of providing treatment of septic shock in a center familiar with the unique needs of pregnant and postpartum woman For example, the American College of the Obstetrician and Gynecologist recommend high-intensity ICU physician staffing for this kind of patients Implement, and appropriate antimicrobial therapy has been associated with worse outcomes In a cohort study of 2,700 adults admitted with septic shock, the interval between onset of hypotension and administration of a antibiotic treatment was inversely proportional to survival Each hour of delay lowered the risk of survival by about 7% In a population-based case-control analysis, using data from the UK obstetrics surveillance system, and the UK confidential inquiry into maternal death, four factors were included in the final regression model Women who died were more likely to have never received antibiotics The points are very important in this, one, the initial choice of antibiotics will be empiric and broad Two, the choice of antibiotic is guided by the most likely pathogen and the severity of the disease And three, local patterns of resistance should be account According with the last surveillance sepsis comparing, empiric combination therapy using at least two antibiotics of different antimicrobial classes aim at the most likely bacteria pathogens for the initial management of septic shock And daily assessment for the escalation of antimicrobial therapy in patients with sepsis and septic shock The 2012 sepsis guidelines is strongly recommend protocolized resuscitation with quantitative endpoints (early goal-directed therapy) With that, substantial evolution has accord in understanding the value of the early goal-directed therapy Three key randomized trials involve patients presenting to their emergency department who have sepsis, with shock or hypoperfusion The PROCESS, PROMISE, and ARISE trials have created substantial uncertainty in how to guide clinicians managing patients with sepsis and septic shock They came together to decide early-goal directed therapy is safe if not superior to not protocolized care, wash out care has evolved since this trial to include more aggressive fluid resuscitation Meta-analysis of [inaudible] patients that have found through recent trials were designed prospectively to improve statistical power and explore heterogeneity of three main effects early-directed therapy The primary outcome of 90-day mortality doesn’t change between early goal-directed therapy and the three studies

Nevertheless, we must work to understand more of their process and start early, give antibiotics, correct hypovolemia, and restore perfusion pressure And at that time, management of sepsis has changed In three studies patients had early antibiotics plus 30ml/kg of intravenous fluids prior to randomization For the recent Surviving Sepsis Campaign recommend, resuscitation from sepsis-induced hypoperfusion, at least 30ml/kg of intravenous crystalloid fluid be given within the first three hours And follow initial resuscitation, additional fluids be guided by frequent reassessment of hemodynamic status Crystalloids are the fluid of choice for initial resuscitation and subsequent intravascular volume replacement, and we can use albumin in addition to crystalloids when patients require substantial amounts of crystalloids The message in the first three hours is early vasopressors The campaign suggests initial target mean arterial pressure of 65mm of mercury in patients with septic shock requiring vasopressor because the evidence has demonstrated that survival doesn’t change with high-risk endpoint Other important points are, norepinephrine as the first-choice vasopressors and they suggest dynamic over static variables be used to predict fluid responsiveness where available Resuscitation to normalize lactate in patients with elevated lactate levels as a marker of tissue hypoperfusion Although the recommendation is mean arterial pressure starting at 65, it will often be too high for particularly healthy young patient and is almost certainly too high in pregnancy Fortunately, many pregnant patients have another measure of perfusion regularly available in the form of the fetal heart rate tracing This is sensitive to placental perfusion Norepinephrine has been used to maintain blood pressure under regional anesthesia for cesarean delivery at, at least at low doses seems to be safe Safety profile comes from a single-cotyledon model of human placenta and did not affect profusion of the fetal side The clinician should not hesitate to administer norepinephrine for a patient with septic shock during pregnancy In the [inaudible] with septic shock in the New York State Department of Health [inaudible] model were used to assess the association between the time to completion of the 3-hour bundle and risk-adjusted mortality More rapid completion of the 3-hour bundle of sepsis care, a rapid use of administration of antibiotics were associated with lower risk-adjusted mortality but not the rapid completion of an initial bolus of intravenous fluid Finally, in the first six hours, very important to define source control Many cases of septic cession are amenable to source control because the source can be often identified and is often accessible to drainage or evacuation Source control is especially crucial in septic abortion And patients who is still pregnant have more risk of spontaneous preterm birth and potential need for delivery as a component of therapy The end of pregnancy depends on many factors and for a cesarean delivery is not routinely indicated and should be reserved for usual obstetric indications I hope we can contribute to improve the health of our women so they can enjoy a beautiful life with their kids like me Thank you Thank you, Maria, I think you covered a lot of information in that short time We are grateful for that We have time for a few questions So the first question relates to lactate measurement, so this is clearly a very important part of the way that you manage your patients, and the question relates to its role in very poor settings where it may not be possible to do lactate measurements, what would be your approach in that setting? Yes, we know that in many low-income countries there is a

problem with access to lactate measurement but one thing is, [inaudible], we define [inaudible], we see differences with a clinical findings but in all the conversations the clinical findings is not enough to be sure about how critical is your patient Another option is try to move all these resources and [inaudible] to obtain a test, is a more safe test in a not so expensive, actual test that is probably one of the conditions why we don’t have the option in many low-resource hospital Thank you. Thank you, Maria There is a question that, or comment rather that early goal-directed therapy, the available evidence didn’t really demonstrate any uncertainty but it showed its failings very clearly What’s your view on that, please? The early goal-directed therapy, probably move the world toward a direction in the resuscitation of bundles or in resuscitation treatment, and the thing is that all the stories of early goal-directed setup, [inaudible] used the best approach using resuscitation and the early treatment with antibiotics And there’s was one report in the evidence in why we have all these kinds of different because the most change after these started probably is one of the reasons Thank you so much, Maria We will stop there but there are questions coming in at the moment, so I very much hope that you will be able to stay on to address some of those later on in the day So we will move onto the next talk, the fourth one and this relates to some exciting work that Mercedes Bonet at WHO is doing So this relates to the Global Maternal Sepsis Study Mercedes is a neonatal health immunologist based in the Department of Reproductive Health and Research at the World Health Organization She has extensive experience in global health with a particular interest in maternal and neonatal infections, care during childbirth, breastfeeding practices and very premature babies Mercedes is currently leading a global study to assess the burden and the management of potential severe maternal infections and sepsis in health care facilities Over to you Mercedes Good morning, good afternoon, good evening everyone I will present you the Global Maternal Sepsis Study and Awareness Campaign And this is the first research activity under the umbrella of the Maternal Unit of Sepsis initiative launched by WHO, Jhpiego, and other partners last year As we started our work around maternal sepsis, one of the first problems we were facing was the burden of maternal sepsis is not very well known and the members who was the absence of a standard definition and broad criteria to identify the condition As you may know, the WHO proposed a new definition of maternal sepsis, which is in line with the current definition sepsis for the general adult population and considering the whole spectrum of pregnancy from early pregnancy to the postpartum or the post-abortion period But now this definition of maternal sepsis needs to be applied and validated and this is the main objective of the GLOSS study In addition, comments of used in the obstetric population and not of the early warning, of course, or other things to perform poorly in predicting rates of developing

maternal sepsis, or needed to find woman may require critical care due to infection This too have other limitations as in general they have not been validated in different populations in low resource settings To be more specific, they use different variables and cut-off points as trigger for action Another issue is that we don’t know how maternal sepsis is managed, especially in low and middle-income countries We don’t know if people are implementing the specific protocols used and bundles of care proposed for the general adult population and whether these management strategies are effective for maternal sepsis at all And finally, in some settings, the lack of awareness of the risk of sepsis and effective strategies to improve care of women with sepsis are an important barrier to improve maternal but also neonatal outcomes So the Global Maternal Sepsis Study was set to develop and validate two sets of criteria for identification of possible severe maternal infection, the presumed maternal sepsis cases And to develop and validate criteria to then decide and confirm maternal sepsis We also would like to assess the frequency and the outcomes of maternal sepsis in developing and developed countries And to assess the frequency of use of a core set of practices recommended for the prevention, early identification, and management of maternal sepsis The secondary objectives are to contribute to the understanding of vertical transmission of bacterial infection by assessing outcomes and management of neonates born to mothers with suspected or confirms infections And lastly, to explore the level of awareness about maternal and neonatal sepsis among health care providers, policymakers, and general public, including pregnant women, mothers, and their families The study is based on the premise that inpatient management is the optimal treatment for a woman with sepsis And in this sense, the health facility is the place where those women will be treated for complication of infections during pregnancy, the intrapartum period, or postpartum, post-abortion period Even in places with low coverage of institutional births The identification of cases and articulation will be prospective, so we will have comparable data and indicators across the all the facilities and countries, which will participate in this study, and this will also allow us to collect early clinical indicators for each facility, clinical science laboratory tests, but also other measurements such as lactate or pulse oximetry if they are available from the medical records, and routinely performed in the facilities participating in this study We will include cases over a week and this will minimize the viability of events across the days of a week, given variations in maternity unit activities, for example, client induction or have a cesarean section on certain days of the week or less staff during the weekend And because some women won’t return to the maternity unit where they gave birth, if they have complication after discharge from hospital and sometimes may not go to an obstetric unit, we aim to cover all facilities where women could be admitted to maximize the identification of eligible cases and in particularly those during the postpartum period Massive data collection will take place to recruit women presenting with infection morbidities during one week between November 28 and December 4th this year, in hundreds of health facilities across 54 countries, across all the

regions of the world – the Americas, Africa, the eastern Mediterranean, Europe, South Asia and the western Pacific In each country, we want a workable area with about 2 million inhabitants will participate in the survey, in each of the participating geographical areas, all health facilities where eligible women could be admitted will be included in the study And before the study, an awareness campaign targeting health care providers will be deployed in this participating facility The campaign will help providers to then decide and treat women at risk of developing sepsis Having this large sample and including a lot of health care facilities have several advantages Given the relative low frequency of maternal sepsis at these facilities, a large collaborated network facilities may ensure an adequate sample size and also the applicability of our findings to other populations By expanding the geographical viability, we will be able to cover different organization of the health system and also limit the effect of geographical or system clusters of infection morbidities This will also help us to reduce the burden of that collection and cost in each country and also in each health facility But having this large network of facilities will also provide us the opportunity to reach more health care providers with an awareness campaign that we will implement before this study So how are we going to identify women for this study? They have to present with any suspected or confirmed clinical infection, as reported by the clinicians during the current hospital stay, that can be a primary admission or a readmission, with or without organ-dysfunction She could also present any clinical signs suggestive of infection, there could be a request for any body fluid culture or swabs, she could be receiving non-prophylactic antibiotics, could have any healthcare-associated infections, for example a womb infection, can have an unexplained organ-dysfunction by other conditions such as hemorrhage for example, and any maternal death at admission or during hospital, that could be aggravated by a suspected or confirmed infection We will also collect information on all babies born to included women By doing this we will be covering the infections as the underlying cause or as a contributing cause of morbidity and maternal mortality Once we have decide these women, we will follow them up until discharge from hospital, from 42 days postpartum, post-abortion, or death, whichever, of course, first And the babies will be followed up for the first week of life, discharge or death, even if they are transferred to another facility in the same geographical area This study will allow us to include around 2,800 women presenting maternal infections, and this is applying birthrate at the global level of 19 and using an estimation of 7% of infections in the population The outputs of this study

We will have a good assessment of the frequency of maternal sepsis We will be able to test the identification criteria, which could be applicable in low-resource settings, for two different states of the condition To identify women with possible severe infections that will allow clinicians to treat her action, for example, a bundle of care specific to maternal sepsis, and also to identify the confirmed cases of maternal sepsis to be recorded and reported and the facility level We will also be able to have an assessment of the frequency of early neonatal sepsis among babies born to mothers with peripartum infection and also how those women are currently managed in the facility The material of the awareness campaign will be also available to be used in other hospitals outside the study At the end, we will have an active network of health facilities and researchers ready to contribute to the reduction of deaths due to infections in mothers and babies I would like to thank the funders of the study and a special thanks to all the people in the ground who are making this study possible, especially our country coordinators and the health care facilities participating in this study Thank you Thank you very much, Mercedes, for sharing this very exciting work that is to come very soon One of the audience members has summed it up very nicely where he mentioned that the challenges are great but a great deal of learning can occur in this week So I think that sums it up We have time for one question So the question is, in terms of trying to achieve coverage, would there be difficulties in private sector hospitals, so that you can’t have a true representation of sepsis morbidity? Yes, so that’s why we are focusing on a geographical area, to be able to capture the whole spectrum of cases that could be admitted in a different facilities and also those women who will be transferred from one facility to the other it is true that by focusing on the health facilities we will mainly have the more severe cases and that we will probably lose the less severe cases or women who died before arriving to our referral facility Thank you so much, Mercedes And again, we hope that you will be able to stay on for the discussions at the end of the session So that takes us to the final talk of the second session of this conference And this final talk is on addressing maternal sepsis in low and middle-income countries And this talk will be given by Jeffery Smith, Dr. Jeffery Smith from Jheipgo in the United States So Dr. Jeffery Smith is an obstetrician and gynecologist and a public health practitioner with over 25 years of clinical and public health experience in developing countries across Asia, Africa, and Latin America He works for Jheipgo as the Vice President for Technical Leadership and that is based in Baltimore, and until recently was also the maternal health team leader at the USA-supported Maternal and Child Survival Program in Washington DC He is also Assistant Professor of Gynecology and Obstetrics at the John Hopkins University School of Medicine Over to you Jeff Great, thank you very much, Arri Good morning, good afternoon, good evening to everyone So I would like to take this opportunity to present a bit

on the situation of maternal infections in resource-limited settings And especially looking at some of the policies and the program dynamics about this when look to make changes and support our colleagues throughout the world I will look at briefly about what we know regarding policy and practice, and where are some of the gaps in low and middle-income countries, where there are some opportunities and what is currently under development in the problematic realm So I think all of the previous speakers have made it a challenge to [inaudible] maternal mortality and the contribution of sepsis to that In a very interesting panel that I was on at the FIGO conference 2015, there were two presentations, one by a colleague from Rwanda and another by a colleague from Uganda who had said because of their concerted efforts over years to address causes of mortality such as hemorrhage and preeclampsia, sepsis and infectious morbidity had become the number one cause of mortality, maternal mortality at their facility So we have a situation where a lot of attention has gone to other causes of maternal mortality over the years and we must as the global community turn our attention towards infection We at Jheipgo conducted a literature review in 2015 looking at causes of infection and also what were the problematic and policy approaches to addressing that And we found, first of all, a sharp lack of specific literature from developing and low, middle-income countries That’s why I think the study that is currently underway, as described by Dr Bonet a moment ago is really critical to our field Also what was noted in this literature review was that was a real difference in terms of the cause of infection, or the perception of the cause of infection between high income countries where people believe prolonged labor and prolonged rupture of membranes was the cause and in lower, middle-income countries where the cause was thought to be hygiene of the facility, hand hygiene, and women’s hygiene specifically So I think this current study that’s underway is useful for us in terms of understanding the ideology If we look at the situation of maternal infection among many different countries and the current efforts being made globally to address maternal health, we find that many of the strategies of bringing women in facilities for [inaudible] their delivery, may contribute to increasing infections Many facilities do not have proper infection prevention protocols, movement into facilities may increase caesarean infection rates, would contribute to infection, the crowding in facilities and the lack of staff may also contribute, and also there maybe because of crowding, women may choose to go home early and that early discharge may result in diagnosis after leaving the facility And the response to infection in recent years has really been limited We have no great new innovation in this area, there are no new drugs or antibiotics that are widely available, no new protocols, and I think this is against the rising rates which I described previously Through the Maternal and Child Survival Program, several years ago, we looked at policies and practices across multiple different countries, and we noted that across 20 different countries, mostly in Africa, Asia, and Latin America, we looked at the policy of whether prophylaxis antibiotics were routinely recommended before manual removal of placenta, and only in 60% of those countries was that the case in national norms and standards The similar data was found for looking for the use of

prophylactic antibiotics before cesarean sections 70% of the countries had policies and guidelines for recommendation of prophylactic antibiotics but 30% of countries did not have that as a policy within their national guideline We also, across five different countries in east and southern Africa, did direct clinical observations regarding infection prevention practices And across more than 2,000 direct observations of clinical care, we saw that in the majority of situations, providers did not wash their hands before examination or before examination during the first stage While they did wear gloves, or put on protective equipment, there was not a routine use of good infection prevention practices across all these facilities and in all these clinical situations Which reminds us that we have to not only be looking at diagnosis and management of infection, we also need to think about preventative practices So what is the current situation regarding maternal infection? We have guidelines that do have appropriate recommendations regarding use of antibiotics but they’re not always specific and they are inconsistently followed And in general, our country programs have prioritized addressing other causes of maternal mortality and morbidity and therefore there has not been much priority placed upon addressing maternal infection Antibiotic use in some situations, it is overused, or use of an indicated antibiotics and in other situations inappropriate use or wrong use of antibiotics So we have to work harder to address both the prevention and management From a program point of view, when we think about typical constellations of interventions, such as basic emergency obstetric care, and comprehensive emergency obstetric care, we have to ask ourselves, where is the management of maternal sepsis in these packages? I think we have to recognize that concentrated capacity building in the management of maternal sepsis have not typically been part of either one of these packages So as we learn more, following this week data collection that Mercedes described, I think we have to revisit the approaches that we take, programmatically and in terms of policy in countries around the world What are the opportunities for improvements in this area? WHO and many implementing partners have recently turned greater attention towards the quality of care Not only for intrapartum care but during antenatal, and postnatal care And therefore, we should join that global effort on addressing quality of care and begin to build stronger infection prevention and management strategies across the pregnancy continuum In terms of prevention, we should look at the antenatal period as an opportunity to optimize women’s health, identify potential infections and address those infections so that women enter labor without risk factors that increase their possibility of intrapartum infection We should be an emphasis on earlier diagnosis of infection and earlier diagnosis of possible sepsis as noted by previous speakers And I think we should begin to look much more critically at treatment options The current treatment options that are recommended in the Managing Complications in Pregnancy and Childbirth manual, talk about a three-drug regimen using ampicillin, gentamycin, clindamycin and metronidazole, all being intravenous drugs with different dosing intervals, which means that the current recommendations require the administration of three different drugs across eight different periods This is a challenge for nurses who are in the postpartum domain, and in postpartum wards, having to care for many patients

And if we look at our colleagues in the newborn field, they have been working to simplify and improve the approaches that they’re taking to infection prevention There is current work underway in a program that we have initiated to address post-cesarean infection by working on a package of intervention Including prophylactic antibiotics, tailored to cesarean infection, appropriate abdominal skin preparation, vaginal wash using chlorhexidine, proper tissue oxygenation and then good surgical technique and asepsis Using this package and an audit and feedback cycle, we hope to be able to drive down post-cesarean infection rates across 40 hospitals in western Tanzania And so, we will report on these results in the coming year Finally, what should we be doing when we think about addressing program approaches to managing sepsis? We have to support the dissemination of the new sepsis definition That definition simplifies and makes it easier for providers to identify and respond early to sepsis We have to support colleagues such as Dr. Lissauer and the work on development and testing of bundles for addressing sepsis And we need to begin to use more team-based approaches to aggressively approach situations where sepsis is suspected We certainly need greater innovation for diagnostics, for management protocols, and for simplifying treatment But together, I think, as we put greater emphasis on addressing maternal infection, maternal sepsis, and early newborn infection, together as programmatic community, I believe that we can make a big impact in this continuing cause of maternal morbidity and mortality So I thank you for your attention, and I look forward to hearing additional comments regarding how we move the maternal infection agenda forward Thank you very much, Jeff, that was a wonderful summary at the end of your presentation And you’ve also laid out the steps for moving forward there Thanks for doing that This takes us to the general discussion session But before we move onto that, Jeff, if I may ask you a question that has been put forward by one of the audience members You said attention in on focusing on one subject area, such as sepsis, and it’s impact on overall quality improvement and other conditions That’s a great question, Arri I think we as a global community have to begin to identify new techniques and approaches that can be added to a broad package of management strategies, for all causes of maternal mortality I think that attention on sepsis should not mean that we should decrease our focus on other causes of maternal mortality so that we’re really adding new approaches and new responses and innovation to a broad package to improve the quality of care I think we’ve in a number of countries, that if we simply encourage women to come to facilities for assisted, for attendant at delivery, but don’t address quality of care comprehensively, we won’t achieve the gains in mortality reduction that we seek So thank you so much, Jeff So that allows us to move onto the discussion session Now this will be brief We’ve in fact got nine minutes to have a discussion So I believe that all the speakers are on the line at the moment So I’ll pick out some questions that have been coming through over the session and I’ll put it to all of you So the first relates to innovations and there are quite a few questions on that Could perhaps, David, comment on what do you think would be key innovations moving forward?

Hi, thanks, Arri Yeah, I think there’s potential for innovation in a number of domains and I think we’ve heard reference to some of these already I think some of the areas around improved sepsis detection, innovation to enable wider use of existing technologies like pulse oximetry, and bedtime lactate measurement and also making existing devices more robust, easier to use so that routine observations are carried out more reliably and consistently But I also think there’s a lot of potential for innovation around the way we implement existing guidelines and innovative quality improvement approaches to make it easier for practitioners on the ground to identify sepsis and manage it appropriately I’m sure others may have additional thoughts Okay. There are a number of quite specific questions and I’m happy for anyone of you to tackle this You say any evidence for the use of procalcitonin to help start or stop antibiotic treatment in maternal sepsis I’m not sure if anyone else that I don’t know of any specific evidence in maternal sepsis, I’m afraid Okay. And what about the role of shock index as a tool for early diagnosis of maternal sepsis Another question I take the shock index question This is Joao Paulo from WHO The shock index from what we have seen in the work on postpartum hemorrhage seems to be promising indicator and we will certainly test this as a potential predictor of maternal sepsis and possible severe maternal infections as part of the study that we discussed before, the GLOSS study We need to do further research to determine its value for maternal sepsis particularly And I think we will achieve in the next couple of months Thank you Thank you, JP So there’s a question for Maria, what is role of vasopressor to maintain mean arterial pressure? So that’s one of the questions from the audience Hello, thank you The role of vasopressor is try to maintain their adequate main arterial pressure to perfusion And the endpoint used in one of the studies is the 65 mm of mercury, and these are specialist study that proves that’s it’s a very good endpoint because highest endpoint doesn’t work in most mother in mortality There is not special study with the use of vasopressor except to show during pregnancy And the reason why many studies in pregnant population suggest the use of the fetal heart rating like another indicator of maternal perfusion Thank you A question to Jeff So we appreciate how important hand washing and infection prevention is, but even when soap and water is available, the uptake of it seems to be limited, what insights can you share from the field to improve it? Thank you I think quality improvement approaches, there are a number of different methodologies and techniques for addressing quality and improvement approaches and hand washing is one of the techniques that has really been highlighted for addressing prevention of infection Making it easy, making it routine, allowing other members of the staff to support other team members

and encouraging people to comment to their colleagues about the need for additional hand washing are all approaches that have been taken into account The other, as I noted, one of the approaches, which is audit and feedback, of tracking certain data, be it infection rates or sepsis, or postpartum infection rate, as a way forwards or facilities to know their specific rates has been useful in helping teams to address behaviors needed to reduce infection Quite. Thank you, Jeff Now we have got only a few minutes, so a final question to Mercedes Mercedes, it is expected that your study will produce lots of exciting findings What do you hope to do with it moving forward? So I think the main outcome of the study will be on helping people to better identify developing sepsis And being able to use, for example, the bundle that David presented or any other package of intervention We will also have data on antimicrobial resistance for example that we will also use here in the organization to move forward this issue Great, thank you, Mercedes So we’ve had a set of wonderful presentations, truly tremendous and the discussions have been very helpful So I would like to thank all the speakers for sharing your knowledge and time with us I would also like to thank our sponsors and of course, the organizers, Global Sepsis Alliance and the World Health Organization for putting this together, which has been a great conference so far But finally, and importantly, of course, the audience, thank you so much for joining us There are more than 7,000 of you from over 100 countries online at the moment, and I think that is truly wonderful We really appreciate this We hope that you found the discussions and the talks useful Please do take this further, have discussions about what you heard with your colleagues and team, and do ponder over what it means to you and to your team, and how this may be taken to your practice to improve outcomes So I think we will conclude there So in a few minutes, we will have the next session, which will be on the crucial subject neonatal success, an exciting lineup there So please stay on for that session But for now, I will thank you and say goodbye Thank you