Critical Care Services for Pregnant Patients in Ontario: A province-wide survey.

Critically ill pregnant patients require advanced critical care support, but access to these services is variable. We surveyed active Ontario obstetric facilities regarding critical care access. Responses were received from 44 of 80 obstetric units (55%), 13 (30%) being rural. Transport to another facility was required by 59% (majority >1 hr transport time), and differences were noted in the availability of specialty support services such as anesthesia and internal/obstetric medicine, as well as radiology and laboratory facilities, and use of massive transfusion protocols. Training in early supportive care of obstetric complications and optimized facility transport are areas for potential improvement.

Acute Respiratory Failure in Pregnancy.

Respiratory failure may affect up to 1 in 500 pregnancies, due to pregnancy-specific conditions, conditions aggravated by the pregnant state, or other causes. Management during pregnancy is influenced by altered maternal physiology, and the presence of a fetus influencing imaging, and drug therapy choices. Few studies have addressed the approach to invasive mechanical ventilatory management in pregnancy. Hypoxemia is likely harmful to the fetus, but precise targets are unknown. Hypocapnia reduces uteroplacental circulation, and some degree of hypercapnia may be tolerated in pregnancy. Delivery of the fetus may be considered to improve maternal respiratory status but improvement does not always occur.

Limiting life-sustaining treatment for very old ICU patients: cultural challenges and diverse practices.

BACKGROUND: Decisions about life-sustaining therapy (LST) in the intensive care unit (ICU) depend on predictions of survival as well as the expected functional capacity and self-perceived quality of life after discharge, especially in very old patients. However, prognostication for individual patients in this cohort is hampered by substantial uncertainty which can lead to a large variability of opinions and, eventually, decisions about LST. Moreover, decision-making processes are often embedded in a framework of ethical and legal recommendations which may vary between countries resulting in divergent management strategies. METHODS: Based on a vignette scenario of a multi-morbid 87-year-old patient, this article illustrates the spectrum of opinions about LST among intensivsts with a special interest in very old patients, from ten countries/regions, representing diverse cultures and healthcare systems. RESULTS: This survey of expert opinions and national recommendations demonstrates shared principles in the management of very old ICU patients. Some guidelines also acknowledge cultural differences between population groups. Although consensus with families should be sought, shared decision-making is not formally required or practised in all countries. CONCLUSIONS: This article shows similarities and differences in the decision-making for LST in very old ICU patients and recommends strategies to deal with prognostic uncertainty. Conflicts should be anticipated in situations where stakeholders have different cultural beliefs. There is a need for more collaborative research and training in this field.

COVID-19 critical illness in pregnancy.

Although the pregnant population was affected by early waves of the COVID-19 pandemic, increasing transmission and severity due to new viral variants has resulted in an increased incidence of severe illness during pregnancy in many regions. Critical illness and respiratory failure are relatively uncommon occurrences during pregnancy, and there are limited high-quality data to direct management. This paper reviews the current literature on COVID-19 management as it relates to pregnancy, and provides an overview of critical care support in these patients. COVID-19 drug therapy is similar to that used in the non-pregnant patient, including anti-inflammatory therapy with steroids and IL-6 inhibitors, although safety data are limited for antiviral drugs such as remdesivir and monoclonal antibodies. As both pregnancy and COVID-19 are thrombogenic, thromboprophylaxis is essential. Endotracheal intubation is a higher risk during pregnancy, but mechanical ventilation should follow usual principles. ICU management should be directed at optimizing maternal well-being, which in turn will benefit the fetus.

Inclusion of pregnant and breastfeeding women in nonobstetrical randomized controlled trials.

BACKGROUND: There is an urgent need to prioritize and expedite the inclusion of pregnant and breastfeeding women in research. Characterizing trials that have successfully included these populations could inform the design and execution of future studies. In addition, up-to-date data on their inclusion in clinical research could assist in setting benchmarks, establishing targets, and monitoring progress toward more equitable inclusion. OBJECTIVE: This study aimed to characterize the eligibility and enrollment of pregnant and breastfeeding women in randomized controlled trials evaluating interventions for nonobstetrical conditions experienced by, but not limited to, these populations. STUDY DESIGN: We developed a literature search in collaboration with an information specialist. We included randomized controlled trials published between 2017 and 2019 in the 5 highest-impact general medicine journals and the 3 highest-impact specialty journals in cardiovascular disease, critical care, general infectious diseases, HIV, and psychiatry. We included randomized controlled trials that evaluated screening, diagnosis, prevention, or treatment of nonobstetrical medical conditions. We excluded randomized controlled trials exclusively focused on males, pediatrics, geriatrics, oncology, or postmenopausal women, and publications reporting subgroup, pooled, or follow-up analyses of previously published randomized controlled trials. We screened titles and abstracts independently and in duplicate, with discrepancies resolved by a third reviewer. We entered data into a standardized electronic case report form. We reviewed study protocols, appendices, and trial registries for additional data. RESULTS: Of the 1333 randomized controlled trials, pregnant and breastfeeding women were eligible for 13 (1.0%) and 6 (0.5%), respectively. Pregnancy and breastfeeding eligibility criteria were not addressed in 383 of 1333 (28.7%) and 710 of 1333 (53.3%) randomized controlled trials, respectively. In total, 102 of 937 (10.9%) and 33 of 617 (5.3%) randomized controlled trials that explicitly excluded pregnant and breastfeeding women documented the rationale. Most studies excluding pregnant women (542/937; 57.8%) required at least 1 method of contraception and/or pregnancy testing as part of trial participation for women with reproductive capacity. Among the 13 randomized controlled trials that allowed inclusion of pregnant women, 3 restricted eligibility to specific trimesters. Two randomized controlled trials enrolled pregnant women after the first year of the study following interim review of safety results in nonpregnant participants. Four randomized controlled trials reported the number of pregnant women enrolled, which ranged from 0.7% to 3.4% of the study population. None of the studies reported on pregnancy or perinatal outcomes. Compared with randomized controlled trials that excluded pregnant women, those including them more commonly had an infectious disease focus (12/13 [92.3%] vs 270/937 [28.8%]; p<.0001), including HIV (5/13 [38.5%] vs 96/937 [10.2%]; p=.0079), enrolled participants in sub-Saharan Africa (5/13 [38.5%] vs 111/937 [11.8%]; p=.0143), and had exclusively nonindustry sponsorship (13/13 [100%] vs 559/937 [59.7%]; p=.0025); inclusion varied by study phase, randomization level, and intervention type. CONCLUSION: This study illustrates a major inequity in research involving pregnant and breastfeeding women. As new health challenges arise, including novel pandemics, and the research community mobilizes to develop therapies and innovate in patient care, it is crucial that pregnant and breastfeeding women not be left behind. Greater regulatory support, in the form of explicit requirements and incentives, will be needed to ensure these populations are integrated into the research agenda.

Clinical decision analysis of elective delivery vs expectant management for pregnant individuals with COVID-19-related acute respiratory distress syndrome.

BACKGROUND: Pregnant individuals are vulnerable to COVID-19-related acute respiratory distress syndrome. There is a lack of high-quality evidence on whether elective delivery or expectant management leads to better maternal and neonatal outcomes. OBJECTIVE: This study aimed to determine whether elective delivery or expectant management are associated with higher quality-adjusted life expectancy for pregnant individuals with COVID-19-related acute respiratory distress syndrome and their neonates. STUDY DESIGN: We performed a clinical decision analysis using a patient-level model in which we simulatedpregnant individuals and their unborn children. We used a patient-level model with parallel open-cohort structure, daily cycle length, continuous discounting, lifetime horizon, sensitivity analyses for key parameter values, and 1000 iterations for quantification of uncertainty. We simulated pregnant individuals at 32 weeks of gestation, invasively ventilated because of COVID-19-related acute respiratory distress syndrome. In the elective delivery strategy, pregnant individuals received immediate cesarean delivery. In the expectant management strategy, pregnancies continued until spontaneous labor or obstetrical decision to deliver. For both pregnant individuals and neonates, model outputs were hospital or perinatal survival, life expectancy, and quality-adjusted life expectancy denominated in years, summarized by the mean and 95% credible interval. Maternal utilities incorporated neonatal outcomes in accordance with best practices in perinatal decision analysis. RESULTS: Model outputs for pregnant individuals were similar when comparing elective delivery at 32 weeks' gestation with expectant management, including hospital survival (87.1% vs 87.4%), life-years (difference, -0.1; 95% credible interval, -1.4 to 1.1), and quality-adjusted life expectancy denominated in years (difference, -0.1; 95% credible interval, -1.3 to 1.1). For neonates, elective delivery at 32 weeks' gestation was estimated to lead to a higher perinatal survival (98.4% vs 93.2%; difference, 5.2%; 95% credible interval, 3.5-7), similar life-years (difference, 0.9; 95% credible interval, -0.9 to 2.8), and higher quality-adjusted life expectancy denominated in years (difference, 1.3; 95% credible interval, 0.4-2.2). For pregnant individuals, elective delivery was not superior to expectant management across a range of scenarios between 28 and 34 weeks of gestation. Elective delivery in cases where intrauterine death or maternal mortality were more likely resulted in higher neonatal quality-adjusted life expectancy, as did elective delivery at 30 weeks' gestation (difference, 1.1 years; 95% credible interval, 0.1 - 2.1) despite higher long-term complications (4.3% vs 0.5%; difference, 3.7%; 95% credible interval, 2.4-5.1), and in cases where intrauterine death or maternal acute respiratory distress syndrome mortality were more likely. CONCLUSION: The decision to pursue elective delivery vs expectant management in pregnant individuals with COVID-19-related acute respiratory distress syndrome should be guided by gestational age, risk of intrauterine death, and maternal acute respiratory distress syndrome severity. For the pregnant individual, elective delivery is comparable but not superior to expectant management for gestational ages from 28 to 34 weeks. For neonates, elective delivery was superior if gestational age was ≥30 weeks and if the rate of intrauterine death or maternal mortality risk were high. We recommend basing the decision for elective delivery vs expectant management in a pregnant individual with COVID-19-related acute respiratory distress syndrome on gestational age and likelihood of intrauterine or maternal death.

Feasibility of establishing a Canadian Obstetric Survey System (CanOSS) for severe maternal morbidity: a study protocol.

INTRODUCTION: Severe maternal morbidity (SMM)-an unexpected pregnancy-associated maternal outcome resulting in severe illness, prolonged hospitalisation or long-term disability-is recognised by many, as the preferred indicator of the quality of maternity care, especially in high-income countries. Obtaining comprehensive details on events and circumstances leading to SMM, obtained through maternity units, could complement data from large epidemiological studies and enable targeted interventions to improve maternal health. The aim of this study is to assess the feasibility of gathering such data from maternity units across Canadian provinces and territories, with the goal of establishing a national obstetric survey system for SMM in Canada. METHODS AND ANALYSIS: We propose a sequential explanatory mixed-methods study. We will first distribute a cross-sectional survey to leads of all maternity units across Canada to gather information on (1) Whether the unit has a system for reviewing SMM and the nature and format of this system, (2) Willingness to share anonymised data on SMM by direct entry using a web-based platform and (3) Respondents' perception on the definition and leading causes of SMM at a local level. This will be followed by semistructured interviews with respondent groups defined a priori, to identify barriers and facilitators for data sharing. We will perform an integrated analysis to determine feasibility outcomes, a narrative description of barriers and facilitators for data-sharing and resource implications for data acquisition on an annual basis, and variations in top-5 causes of SMM. ETHICS AND DISSEMINATION: The study has been approved by the Mount Sinai and Hamilton Integrated Research Ethics Boards. The study findings will be presented at annual scientific meetings of the Society of Obstetricians and Gynaecologists of Canada, North American Society of Obstetric Medicine, and International Network of Obstetric Survey Systems and published in an open-access peer-reviewed Obstetrics and Gynaecology or General Internal Medicine journal.

Adapting obstetric and neonatal services during the COVID-19 pandemic: a scoping review.

BACKGROUND: The provision of care to pregnant persons and neonates must continue through pandemics. To maintain quality of care, while minimizing physical contact during the Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV2) pandemic, hospitals and international organizations issued recommendations on maternity and neonatal care delivery and restructuring of clinical and academic services. Early in the pandemic, recommendations relied on expert opinion, and offered a one-size-fits-all set of guidelines. Our aim was to examine these recommendations and provide the rationale and context to guide clinicians, administrators, educators, and researchers, on how to adapt maternity and neonatal services during the pandemic, regardless of jurisdiction. METHOD: Our initial database search used Medical subject headings and free-text search terms related to coronavirus infections, pregnancy and neonatology, and summarized relevant recommendations from international society guidelines. Subsequent targeted searches to December 30, 2020, included relevant publications in general medical and obstetric journals, and updated society recommendations. RESULTS: We identified 846 titles and abstracts, of which 105 English-language publications fulfilled eligibility criteria and were included in our study. A multidisciplinary team representing clinicians from various disciplines, academics, administrators and training program directors critically appraised the literature to collate recommendations by multiple jurisdictions, including a quaternary care Canadian hospital, to provide context and rationale for viable options. INTERPRETATION: There are different schools of thought regarding effective practices in obstetric and neonatal services. Our critical review presents the rationale to effectively modify services, based on the phase of the pandemic, the prevalence of infection in the population, and resource availability.

Tocilizumab for coronavirus disease 2019 in pregnancy and lactation: a narrative review.

BACKGROUND: Tocilizumab is a monoclonal antibody that interrupts interleukin-6 signalling, reducing downstream effects on inflammation and the innate immune response. It was shown to reduce mortality in patients with severe or critical coronavirus disease 2019 (COVID-19). Pregnant and breastfeeding people were largely excluded from clinical trials and hence, the extent to which results can be applied to these populations is not clear. OBJECTIVES: To synthesize published data on tocilizumab in pregnancy and lactation, highlight important knowledge gaps, and help inform clinical decision-making about tocilizumab's use in these populations with COVID-19. SOURCES: PubMed was searched for studies evaluating tocilizumab in pregnancy and lactation for COVID-19 and other indications. Literature on pharmacokinetics and reproductive/fetal safety of monoclonal antibodies in general was also sought. The US Food and Drug Administration and the European Medicines Agency guidance for the industry and regulatory approval documents were reviewed. CONTENT: Published data on tocilizumab in pregnancy include 610 cases (n = 20 with COVID-19) together with seven mother-infant breastfeeding pairs. Higher rates of spontaneous abortion and premature birth have been reported compared with the general population, but multiple confounding variables limit interpretation. There is little data on tocilizumab exposure in the second and third trimesters when transplacental transport is highest. The effects of tocilizumab on the developing immune system are unclear. Pregnant patients with COVID-19 who received tocilizumab were often critically ill and corticosteroid use was uncommon. Neonatal follow up was limited. Tocilizumab appears to be compatible with breastfeeding. IMPLICATIONS: Although the available data do not raise serious safety signals, they have significant limitations and are not sufficient to delineate the complete spectrum of potential adverse outcomes that may be associated with tocilizumab exposure during pregnancy and lactation. Diligent follow up and documentation of pregnancy outcomes will be important moving forward. A more effective regulatory framework to ensure equitable inclusion of pregnant people in research is clearly needed.

Characterizing the inclusion of pregnant and breastfeeding people in infectious diseases randomized controlled trials: a targeted literature review.

OBJECTIVES: Severe complications of infectious diseases can occur during pregnancy. Evidence-based prevention and treatment strategies are critical to improve maternal and neonatal health outcomes. Despite this medical need, pregnant and breastfeeding people have been systematically excluded from biomedical research. The objective of this study was to characterize representation of pregnant and breastfeeding people in randomized controlled trials (RCTs) evaluating a broad range of interventions for infectious diseases. METHODS: Pregnancy and breastfeeding inclusion criteria were examined in infectious diseases RCTs published between 1 January 2017, and 31 December 2019, in the top five highest impact general medicine and the top three highest impact infectious diseases and HIV journals. RESULTS: Of 376 RCTs, 5.3% and 1.9% included pregnant and breastfeeding people, respectively. Justification for exclusion was documented in 36/271 (13.3%) studies that explicitly excluded pregnant people. Most studies excluding pregnant people (177/271, 65.3%) required at least one form of contraception, abstinence and/or negative pregnancy test(s) as part of participation. Only 11/271 (4.1%) studies excluding pregnant people allowed participants to continue the intervention if unintended pregnancy occurred during the study. When both pregnant and non-pregnant people were eligible, pregnant people made up <3% of participants. Only 2/48 (4.2%) vaccine studies included pregnant people; 13/234 (5.5%) drug studies included pregnant people. All studies of procedures, devices, behaviour/education and supplements/vitamins explicitly excluded or did not address pregnancy eligibility criteria. Only 2/20 (10.0%) RCTs including pregnant people collected pharmacokinetic data. DISCUSSION: This study demonstrates widespread exclusion of pregnant and breastfeeding people from infectious disease RCTs.

Incidence, morbidity, and associated factors for sepsis in women hospitalized for delivery: a nationwide retrospective observational population-based study in Canada.

PURPOSE: The objective of this research was to examine the epidemiology of maternal sepsis in Canada. METHODS: We conducted a population-based retrospective cohort study of women (≥ 20 weeks gestation) hospitalized for delivery in all Canadian hospitals (excluding Quebec) between 1 April 2004 and 31 March 2017. Data were obtained from the national Canadian Institute for Health Information database and sepsis cases were identified via International Classification of Diseases, Tenth Revision, Canada (ICD-10-CA) codes. Our primary outcome was the number of hospitalizations for delivery associated with maternal sepsis. We further explored associations between patient characteristics, obstetric procedures/conditions, medical conditions, and maternal sepsis. Associations were presented using odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: There were 4,183 cases of sepsis in 3,653,783 hospitalizations for delivery during the study period, with an incidence of 114 (95% CI, 111 to 118) per 100,000 hospitalizations and a mortality rate of 0.5%. Annual sepsis rates per 100,000 hospitalizations ranged from a high of 160 (95% CI, 146 to 177) in 2004 to 94 (95% CI, 83 to 106) in 2011. Highest regional rates were observed in the Territories (224 per 100,000). Severe sepsis was seen in 14% (n = 568) of all patients with sepsis, which was one or more of septic shock (15%; n = 85), organ failure (61%; n = 345), intensive care unit admission (78%; n = 443), or mortality (3%; n = 19). Multivariable models showed that postpartum hemorrhage (OR, 2.9; 95% CI, 2.7 to 3.2), Cesarean delivery (OR, 3.2; 95% CI, 3.0 to 3.5), anemia (OR, 3.9; 95% CI, 3.5 to 4.3), hysterectomy (OR, 4.9; 95% CI, 3.6 to 6.6), chorioamnionitis (OR, 7.6; 95% CI, 6.9 to 8.3), as well as cardiorespiratory, renal and liver conditions were associated with maternal sepsis. CONCLUSION: Maternal sepsis rates have been decreasing in Canada but remain higher than those in the UK and USA. Our study explored associations with maternal sepsis and shows that one in seven women with sepsis develop severe sepsis-related morbidity, which warrants risk stratification and health policy changes.

RéSUMé: OBJECTIF: L'objectif de cette étude était d'examiner l'épidémiologie du sepsis maternel au Canada. MéTHODE: Nous avons mené une étude de cohorte rétrospective basée sur la population de femmes (≥ 20 semaines de gestation) hospitalisées pour accouchement dans tous les hôpitaux canadiens excluant le Québec entre le 1er avril 2004 et le 31 mars 2017. Les données ont été obtenues à partir de la base de données nationale de l'Institut canadien d'information sur la santé et les cas de sepsis ont été identifiés au moyen des codes de la Classification internationale des maladies, dixième révision, Canada (CIM-10-CA). Notre critère d'évaluation principal était le nombre d'hospitalisations pour accouchement associées à un sepsis maternel. Nous avons également exploré les associations entre les caractéristiques des patientes, les interventions / conditions obstétricales, les conditions médicales et le sepsis maternel. Les associations ont été présentées à l'aide de rapports de cotes (RC) et d'intervalles de confiance (IC) à 95 %. RéSULTATS: Il y a eu 4183 cas de sepsis parmi les 3 653 783 hospitalisations pour accouchement au cours de la période à l'étude, avec une incidence de 114 (IC 95 %, 111 à 118) pour 100 000 hospitalisations et un taux de mortalité de 0,5 %. Les taux annuels de sepsis pour 100 000 hospitalisations variaient d'un pic de 160 (IC 95 %, 146 à 177) en 2004 à 94 (IC 95 %, 83 à 106) en 2011. Les taux régionaux les plus élevés ont été observés dans les Territoires (224 pour 100 000). Un sepsis sévère a été observé chez 14 % (n = 568) des patientes atteintes de sepsis. Cette complication s'est manifestée en choc septique (15 %; n = 85), défaillance d'organe (61 %; n = 345), admission aux soins intensifs (78 %; n = 443), ou mortalité (3 %; n = 19), ou en combinaison de ces complications. Des modèles multivariés ont montré que l'hémorragie du post-partum (RC, 2,9; IC 95 %, 2,7 à 3,2), l'accouchement par césarienne (RC, 3,2; IC 95 %, 3,0 à 3,5), l'anémie (RC, 3,9; IC 95 %, 3,5 à 4,3), l'hystérectomie (RC, 4,9; IC 95 %, 3,6 à 6,6), la chorioamnionite (RC, 7,6; IC 95 %, 6,9 à 8,3), ainsi que les affections cardiorespiratoires, rénales et hépatiques étaient associées au sepsis maternel. CONCLUSION: Les taux de sepsis maternel ont diminué au Canada, mais demeurent plus élevés qu'au Royaume-Uni et aux États-Unis. Notre étude a exploré les associations avec le sepsis maternel et montre qu'une femme sur sept atteinte de sepsis développe une morbidité sévère liée au sepsis, ce qui justifie une stratification des risques et des changements dans les politiques de santé.

Physician Perspectives on Including Pregnant Women in Covid-19 Clinical Trials: Time for a Paradigm Change.

Excluding pregnant people from Covid-19 clinical trials may lead to unintended harmful consequences. For this study, an online questionnaire was sent to physicians belonging to Canadian professional medical associations in order to evaluate their perspectives on the participation of pregnant women in Covid-19 clinical trials. The majority of respondents expressed support for including pregnant women in Covid-19 trials (119/165; 72%), especially those investigating therapies with a prior safety record in pregnancy (139/164; 85%). The main perceived barriers to inclusion identified were unwillingness of pregnant patients to participate and of treating teams to offer participation, the burden of regulatory approval, and a general "culture of exclusion" of pregnant women from trials. We describe why some physicians may be reluctant to include pregnant individuals in trials, and we identify barriers to the appropriate participation of pregnant people in clinical research.

A Detailed Review of Critical Care Considerations for the Pregnant Cardiac Patient.

Maternal cardiovascular disease is a leading cause of maternal death worldwide and recently, maternal mortality has increased secondary to cardiovascular causes. Maternal admissions to critical care encompass 1%-2% of all critical care admissions, and although not common, the management of the critically ill pregnant patient is complex. Caring for the critically ill pregnant cardiac patient requires integration of pregnancy-associated physiologic changes, understanding pathophysiologic disease states unique to pregnancy, and a multidisciplinary approach to timing around delivery as well as antenatal and postpartum care. Herein we describe cardiorespiratory changes that occur during pregnancy and the differential diagnosis for cardiorespiratory failure in pregnancy. Cardiorespiratory diseases that are either associated or exacerbated by pregnancy are highlighted with emphasis on perturbations secondary to pregnancy and appropriate management strategies. Finally, we describe general management of the pregnant cardiac patient admitted to critical care.

A review of remdesivir for COVID-19 in pregnancy and lactation.

Mounting evidence suggests that pregnant people have an elevated risk of severe COVID-19-related complications compared with their non-pregnant counterparts, underscoring the need for effective prevention and treatment strategies. However, despite progress in innovative and flexible trial designs during the COVID-19 pandemic, regressive policies excluding pregnant and breastfeeding people from biomedical research persist. Remdesivir, a broad-spectrum antiviral, was the first drug licensed for the treatment of COVID-19, based on data showing it reduced the time to recovery in hospitalized patients. Pregnant and breastfeeding people were specifically excluded from all clinical trials of remdesivir in COVID-19, but data are accumulating from post-marketing registries, compassionate use programmes and case series/reports. In this review we synthesize these data and highlight key knowledge gaps to help inform clinical decision-making about its use in pregnancy and lactation.