Conducta suicida y periodo perinatal: entre el tabú y la incomprensión / Suicidal behavior and the perinatal period: taboo and is understanding

El suicidio es la primera causa de muerte de las mujeres durante el periodo perinatal, que comprende desde el embarazo hasta un año después del parto. Hay apoyo empírico suficiente para afirmar que las mujeres embarazadas tienen mayor ideación suicida que su correspondiente grupo de comparación en la población general. A pesar de estos datos, este tipo de problemas no suelen ni prevenirse ni reconocerse adecuadamente. Sin embargo, si las disonancias y dilemas asociados a la maternidad, así como los problemas de salud mental, no se previenen o se abordan adecuadamente, éstos pueden afectar al bienestar de las mujeres, al de sus hijos y al de otros miembros de la familia. Se exponen los factores implicados en la conducta suicida de este grupo de mujeres, así como algunas directrices generales de actuación. Se reclama la necesaria puesta en marcha de estrategias de prevención. (AU)

Suicide is the leading cause of death for women during the perinatal period, which commences in pregnancy and finishes one year after delivery. Empirical evidence from previous studies shows that pregnant women have greater suicidal ideation than their comparison group in the general population. However, there is a tendency for these problems to be neither prevented nor adequately recognized. Nevertheless, if the dissonancesand dilemmas associated with motherhood, as well as mental health problems, are not prevented or adequately addressed, they can affect thewell-being of women, their children, and other family members. Risk and protective factors for suicidal behavior in this group of women are discussed, as well as general principles of action. The need for the implementation of prevention strategies is highlighted. (AU)

From non-invasive to invasive fetal therapy: A comprehensive review and current update.

"Fetus as patient" indicates fundamental concept of fetal therapy. With advance in maternal serum analysis and fetal imaging, prenatal screening has become standard of care. Accurate diagnosis in early gestation allows intervention to reverse pathophysiology and delay progression immediately. Non-invasive, minimally invasive and invasive therapies demonstrate their therapeutic potential in certain diseases. Recently, stem cell and gene therapies have been developed to avoid irreversible impairment. To elevate efficacy of treatment modality, extensive studies should be conducted according to regulatory authority. Striking a balance between scientific and ethical integrity is essential, so long-term follow up should be arranged for protecting mother and fetus.

Professional integrity in maternal - fetal innovation and research: an essential component of perinatal medicine.

OBJECTIVES: Clinical innovation and research on maternal-fetal interventions have become an essential for the development of perinatal medicine. In this paper, we present an ethical argument that the professional virtue of integrity should guide perinatal investigators. METHODS: We present an historical account of the professional virtue of integrity and the key distinction that this account requires between intellectual integrity and moral integrity. RESULTS: We identify implications of both intellectual and moral integrity for innovation, research, prospective oversight, the role of equipoise in randomized clinical trials, and organizational leadership to ensure that perinatal innovation and research are conducted with professional integrity. CONCLUSIONS: Perinatal investigators and those charged with prospective oversight should be guided by the professional virtue of integrity. Leaders in perinatal medicine should create and sustain an organizational culture of professional integrity in fetal centers, where perinatal innovation and research should be conducted.

The future of Cochrane Neonatal.

Cochrane Neonatal was first established in 1993, as one of the original review groups of the Cochrane Collaboration. In fact, the origins of Cochrane Neonatal precede the establishment of the collaboration. In the 1980's, the National Perinatal Epidemiology Unit at Oxford, led by Dr. Iain Chalmers, established the "Oxford Database of Perinatal Trials" (ODPT), a register of virtually all randomized controlled trials in perinatal medicine to provide a resource for reviews of the safety and efficacy of interventions used in perinatal care and to foster cooperative and coordinated research efforts in the perinatal field [1]. An effort that was clearly ahead of its time, ODPT comprised four main elements: a register of published reports of trials; a register of unpublished trials; a register of ongoing and planned trials; and data derived from pooled overviews (meta-analyses) of trials. This core effort grew into the creation of the seminal books, "Effective Care in Pregnancy and Childbirth" as well as "Effective Care of the Newborn Infant" [2,3]. As these efforts in perinatal medicine grew, Iain Chalmers thought well beyond perinatal medicine into the creation of a worldwide collaboration that became Cochrane [4]. The mission of the Cochrane Collaboration is to promote evidence-informed health decision-making by producing high-quality, relevant, accessible systematic reviews and other synthesized research evidence (www.cochrane.org). Cochrane Neonatal has continued to be one of the most productive review groups, publishing between 25 tpo to 40 new or updated systematic reviews each year. The impact factor has been steadily increasing over four years and now rivals most of the elite journals in pediatric medicine. Cochrane Neonatal has been a worldwide effort. Currently, there are 404 reviews involving 1206 authors from 52 countries. What has Cochrane done for babies? Reviews from Cochrane Neonatal have informed guidelines and recommendations worldwide. From January 2018 through June 2020, 77 international guidelines cited 221 Cochrane Neonatal reviews. These recommendations have included recommendations of the use of postnatal steroids, inhaled nitric oxide, feeding guidelines for preterm infants and other core aspects of neonatal practice. In addition, Cochrane Reviews has been the impetus for important research, including the large-scale trial of prophylactic indomethacin therapy, a variety of trials of postnatal steroids, trials of emollient ointment and probiotic trials [6]. While justifiably proud of these accomplishments, one needs to examine the future contribution of Cochrane Neonatal to the neonatal community. The future of Cochrane Neonatal is inexorably linked to the future of neonatal research. Obviously, there is no synthesis of trials data if, as a community, we fail to provide the core substrate for that research. As we look at the current trials' environment, fewer randomized controlled trial related to neonates are being published in recent years. A simple search of PubMed, limiting the search to "neonates" and "randomized controlled trials" shows that in the year 2000, 321 randomized controlled trials were published. These peaked five years ago, in 2015, with close to 900 trials being published. However, in 2018, only 791 studies are identified. Does this decrease represent a meaningful change in the neonatal research environment? Quite possibly. There are shifting missions of clinical neonatology at academic medical institutions, at least in the United States, with a focus on business aspects as well as other important competing clinical activities. Quality improvement has taken over as one of the major activities at both private and academic neonatal practices. Clearly, this is a needed improvement. All units at levels need to be dedicated to improving the outcomes of the sick and fragile population we care for. However, this need not be at the expense of formal clinical trials. It is understandable that this approach would be taken. Newer interventions frequently relate to complex systems of care and not the simple single interventions. Even trials that might traditionally have been done as randomized controlled trials, such as the introduction of a new mode of ventilation, are in reality complex challenges to the ability of institutions to create systems to adapt to these new technologies. Cost of doing trials has always been a barrier. The challenging regulatory and ethical environment contributes to these problems as well [7]. Despite these barriers, how does the research agenda of the neonatal community move forward in the 21st Century? We need to reassess how we create and disseminate our research findings. Innovative trial designs will allow us to address complex issues that we may not have tackled with conventional trials. Adaptive designs may allow us to look at potentially life-saving therapies in a way that feel more efficient and more ethical [8]. Clarifying issues such as the use of inhaled nitric oxide in preterm infants would be greatly served if we even knew whether or not there are hypoxemic preterm infant who would benefit from this therapy [9]. Current trials do not suggest so, yet current practice tells us that a significant number of these babies will receive inhaled nitric oxide [10-13]. Adaptive design, such as those done with trials of extracorporeal membrane oxygenation (ECMO), would allow us to quickly assess whether, in fact, these therapies are life-saving and allow us to consider whether or not further trials are needed [14,15]. Our understanding that many interventions involve entire systems approaches does not relegate us only to doing quality improvement work. Cluster designs may allow us to test more complex interventions that have usually been under the purview of quality improvement [16-18]. Cluster trials are well suited for such investigations and can be done with the least interruption to ongoing care. Ultimately, quality improvement is the application of the best evidence available (evidence-based medicine is "what to do" and evidence-based practice is "how to do"). [19,20]. Nascent efforts, such as the statement on "embedding necessary research into culture and health" (the ENRICH statement) call for the conduct of large, efficient pragmatic trials to evaluate neonatal outcomes, as in part called for in the ALPHA Collaboration [21,22]. This statement envisions an international system to identify important research questions by consulting regularly with all stakeholders, including patients, public health professionals, researchers, providers, policy makers, regulators, funders of industry. The ENRICH statement envisions a pathway to enable individuals, educational institutions, hospitals and health-care facilities to confirm their status as research-friendly by integrating an understanding of trials, other research and critical thinking and to teaching learning and culture, as well as an engagement with funders, professional organizations and regulatory bodies and other stake holders to raise awareness of the value of efficient international research to reduce barriers to large international pragmatic trials and other collaborative studies. In the future, if trials are to be done on this scale or trials are prospectively designed to be analyzed together, core outcome measures must be identified and standardized. That clinical trials supply estimates of outcomes that are relevant to patients and their families is critical. In addition, current neonatal research evaluates many different outcomes using multiple measures. A given measure can have multiple widely used definitions. Bronchopulmonary dysplasia (or chronic lung disease just to add to the confusion) quickly comes to mind [23,24]. The use of multiple definitions when attempting to measure the same outcome prevents synthesis of trial results and meta-analysis and hinders efforts to refine our estimates of effects. Towards that end, Webbe and colleagues have set out to develop a core outcome set for neonatal research [25]. Key stakeholders in the neonatal community reviewed multiple outcomes reported in neonatal trials and qualitative studies. Based on consensus, key outcome measures were identified, including survival, sepsis, necrotizing enterocolitis, brain injury on imaging, retinopathy or prematurity, gross motor ability, general cognitive ability, quality of life, adverse events, visual impairment or blindness, hearing impairment or deafness, chronic lung disease/bronchopulmonary dysplasia. Trials registration has to be a continued focus of the neonatal community. Trials registration allows for systematic reviewers to understand whether or not reporting bias has occurred [26]. It also allows for transparent incorporation of these core outcome measures. Ultimately, trials registration should include public reporting of all of these core outcomes and, in the future, access to data on an individual level such that more sophisticated individual patient data meta-analysis could occur. Lastly, there is no reason to see clinical trials and quality improvement as separate or exclusive activities. In fact, in the first NICQ Collaborative, conducted by Vermont Oxford Network, participation in a trial of postnatal steroids was considered part of the quality improvement best practices as opposed to simply choosing an as-of-yet unproven approach to use of this potent drug [27]. What role will Cochrane Neonatal play as we move forward in the 21st Century? As the neonatal community moves forward with its' research agenda, Cochrane Neonatal must not only follow but also lead with innovative approaches to synthesizing research findings. Cochrane Neonatal must continue to work closely with guideline developers. The relationship between systematic review production and guideline development is clearly outlined inreports from the Institute of Medicine [28,29]. Both are essential to guideline development; the systematic review group culling the evidence for the benefits and harms of a given intervention and the guideline group addressing the contextual issues of cost, feasibility, implementation and the values and preferences of individuals and societies. Most national and international guidelines groups now routinely use systematic reviews as the evidence basis for their guidelines and recommendations. Examples of the partnership between Cochrane Neonatal and international guideline development can be seen in our support of the World Health Organization (WHO) guidelines on the use of vitamin A or the soon to be published recommendations from the International Liaison Committee on Resuscitation (ILCOR) on cord management in preterm and term infants [30]. In the future, we need to collaborate early in the guideline development process so that the reviews are fit for purpose and meet the needs of the guideline developers and the end users. Towards this end, all Cochrane Neonatal reviews now contain GRADE assessments of the key clinical findings reported in the systematic review [31]. Addition of these assessments addresses the critical issue of our confidence in the findings. We are most confident in evidence provided by randomized controlled trials but this assessment can be can be downgraded if the studies that reported on the outcome in question had a high risk of bias, indirectness, inconsistency of results, or imprecision, or where there is evidence of reporting bias. Information provided by GRADE assessments is seen as critical in the process of moving from the evidence to formal recommendations [32]. We need to explore complex reviews, such as network (NMA) or multiple treatment comparison (MCT) meta-analyses, to address issues not formally addressed in clinical trials [33]. In conditions where there are multiple effective interventions, it is rare for all possible interventions to have been tested against each other [34]. A solution could be provided by network meta-analysis, which allows for comparing all treatments with each other, even if randomized controlled trials are not available for some treatment comparisons [34]. Network meta-analysis uses both direct (head-to-head) randomized clinical trial (RCT) evidence as well as indirect evidence from RCTs to compare the relative effectiveness of all included interventions [35]. However, Mills and colleagues note that the methodological quality of MTCs may be difficult for clinicians to interpret because the number of interventions evaluated may be large and the methodological approaches may be complex [35]. Cochrane Neonatal must take a role in both the creation of such analyses and the education of the neonatal community regarding the pitfalls of such an approach. The availability of individual patient data will make more sophisticated analyses more available to the community. Although the current crop of individual patient data meta-analyses (including the reviews of elective high frequency ventilation, inhaled nitric oxide and oxygen targets) have not differed substantially from the findings of the trials level reviews (suggesting that, in fact, sick neonates are more alike that unalike), there still will be a large role for individual patient data meta-analysis, at least to end the unfound conclusions that these therapies are effective in various subgroups (be it issues of sex, disease severity, or clinical setting) [36-39]. Future trials should take a lesson from the NeOProM Collaborative [37,39]. Given the difficulty in generating significant sample size and creating funding in any single environment, trials with similar protocols should be conducted in a variety of healthcare settings with an eye towards both study level and individual patient level meta-analysis at the conclusion of those trials, allowing for broader contribution to the trials data, more rapid accrual of sample size, and more precise results. We need to educate the neonatal community regarding the use and abuse of diagnostic tests. Diagnostic tests are a critical component of healthcare but also contribute greatly to the cost of medical care worldwide. These costs include the cost of the tests themselves and the costs of misdiagnosis and treatment of individuals who will not benefit from those treatments. Clinicians may have a limited understanding of diagnostic test accuracy, the ability of a diagnostic test to distinguish between patients with and without the disease or target condition [41,42]. Efforts such as Choosing Wisely have tried to identify these deficiencies [40]. As Cochrane has increased the general literacy of both the medical and general population regarding the interpretation of the results of interventions on various diseases, so should Cochrane move forward and improve the understanding of diagnostic testing. We need to become more efficient at creating and maintaining our reviews. The time spent to produce systematic reviews is far too great. In average, it takes between 2½ to 6½ years to produce a systematic review, requiring intense time input for highly trained and expensive experts. Innovations in the ways in which we produce systematic reviews can make the review process more efficient by outsourcing some of the tasks or crowdsourcing to machine learning. We need to let the crowd and machine learning innovations help us sort the massive amounts of information needed to conduct systematic reviews. It can also allow for "live" updating of critical reviews where the research landscape is quickly changing [43]. Lastly, Cochrane Neonatal must focus more on users of the reviews and not necessarily authors of the reviews. Current Cochrane programming speaks of Cochrane training with an eye towards developing the skills of individuals who will conduct systematic reviews. While this is clearly needed and laudable, the fact of the matter is that most of the community will be "users" of the reviews. Individuals who need to understand how to use and interpret the findings of systematic reviews. These review users include clinicians, guideline developers, policy makers and families. Incorporation of GRADE guidelines has been a huge step in adding transparency to the level of uncertainty we have in our findings. From a family's perspective, we need to overcome the environment of mistrust or misunderstanding of scientific evidence and how we convey what we know, and our uncertainty about what we know, to parents and families.

Role of Regulatory T Cells in Regulating Fetal-Maternal Immune Tolerance in Healthy Pregnancies and Reproductive Diseases.

Regulatory T cells (Tregs) are a specialized subset of T lymphocytes that function as suppressive immune cells and inhibit various elements of immune response in vitro and in vivo. While there are constraints on the number or function of Tregs which can be exploited to evoke an effective anti-tumor response, sufficient expansion of Tregs is essential for successful organ transplantation and for promoting tolerance of self and foreign antigens. The immune-suppressive property of Tregs equips this T lymphocyte subpopulation with a pivotal role in the establishment and maintenance of maternal tolerance to fetal alloantigens, which is necessary for successful pregnancy. Elevation in the level of pregnancy-related hormones including estrogen, progesterone and human chorionic gonadotropin promotes the recruitment and expansion of Tregs, directly implicating these cells in the regulation of fetal-maternal immune tolerance. Current studies have provided evidence that a defect in the number or function of Tregs contributes to the etiology of several reproductive diseases, such as recurrent spontaneous abortion, endometriosis, and pre-eclampsia. In this review, we provide insight into the underlying mechanism through which Tregs contribute to pregnancy-related immune tolerance and demonstrate the association between deficiencies in Tregs and the development of reproductive diseases.

Biomarkers of oxidative stress in the fetus and in the newborn.

The dynamic field of perinatology entails ever-increasing search for molecular mechanisms of neonatal diseases, especially in the domain of fetal growth and neurodevelopmental outcome. There is an urgent need for new molecular biomarkers, to early identify newborn at high risk for developing diseases and to provide new treatment targets. The interest in biomarkers of oxidative stress in perinatal period have begun to grow in the last century, when it was evidenced the importance of the free radicals generation underlying the various disease conditions. To date, interesting researches have been carried out, representing milestones for implementation of oxidative stress biomarkers in perinatal medicine. Use of a panel of "oxidative stress biomarkers", particularly non protein bound iron, advanced oxidative protein products and isoprostanes, may provide valuable information regarding functional pathways underlying free radical mediated diseases of newborns and their early identification and prevention. Here, we will review recent advances and the current knowledge on the application of biomarkers of oxidative stress in neonatal/perinatal medicine including novel biomarker discovery, defining yet unrecognized biologic therapeutic targets, and linking of oxidative stress biomarkers to relevant standard indices and long-term outcomes.

Growth charts and prediction of abnormal growth - what is known, what is not known and what is misunderstood.

OBJECTIVES: Assessment of fetal growth has an important effect on perinatal morbidity and mortality. To understand what tool to choose best for a given population a basic knowledge of how growth charts are developed and used has to be acquired. For this reason, this literature review was performed. MATERIAL AND METHODS: An extensive literature review aimed at identifying articles related to the development of growth assessment in both spectrums of abnormal fetal growth - large and small. The analyzed articles were chosen and presented to show both the historical aspects of growth assessment, current trends and future considerations. RESULTS: Identification of both large and small fetuses and neonates is equally crucial. Definitions and methodology vary worldwide and there is an ongoing discussion on the best tool to choose for a given population. An important part of the debate is how to differentiate between the physiologically small fetus and the truly growth restricted fetus who is at risk of perinatal complication. Similarly, the diagnosis of a large fetus is important in prevention of perinatal complications and surgical deliveries. Many clinical settings still lack growth standards. CONCLUSIONS: Birthweight for gestational age charts are biased for weight in preterm birth. Prediction and management of outcome cannot be based solely on fetal size. Small is not the only problem, we have to think large as well. A common misunderstanding in clinical practice is not using uniform charts in defining growth.

CRISPR diagnostics: Underappreciated uses in perinatology.

CRISPR-based therapeutics have the potential to revolutionize the treatment of hereditary diseases, but current efforts to translate research to the bedside face significant technical, regulatory, and ethical hurdles. In this article, we discuss an underappreciated application of CRISPR: diagnostic testing, and argue that: (1) CRISPR diagnostics are poised to disrupt diagnostic practices including perinatal screening and (2) since CRISPR diagnostics pose minimal technical, regulatory and ethical hurdles (unlike CRISPR therapeutic uses) they are likely to be clinically relevant before CRISPR-based therapies, and thus warrant medical community's attention.

Clínicas Perinatológicas Argentinas 2018 / Argentine perinatological clinics 2018

En este número se reúne material sobre perinatología preventiva; dolor del músculo esquelético durante el embarazo; seguimiento del recién nacido de alto riesgo; hiperemesis gravídica; drogas y embarazo; microbioma y epigenética en perinatología; duelo perinatal; y cuidado del recién nacido.

Postpartum hemorrhage with transfusion: Trends, near misses, risk factors and management at the scale of a perinatal network.

OBJECTIVES: To analyze temporal trends and management of postpartum hemorrhage (PPH) with transfusion and its related maternal near-miss (MNM) cases between 2006 and 2014 and to study risk factors. MATERIAL AND METHODS: This retrospective cohort study from two prospective databases included 156,047 women giving birth in all the maternity hospitals of Burgundy. We analyzed temporal trends and the distribution of PPH with transfusion, the circumstances of transfer of patients between hospitals and factors associated with PPH with transfusion. PPH with massive blood transfusion and/or non-medical treatment was defined as MNM. Statistical analysis included Chi2 tests and logistic regression for multivariate analysis. RESULTS: The overall rate of PPH with transfusion was 7.3‰ and globally increased during the study period whereas the MNM rate did not. MNM represented 37% of patients with PPH with transfusion and 71% of transferred patients, but surgical treatments were performed before transfer. Factors associated with PPH with transfusion were maternal age>35 years (odds ratio [OR]=1.3), prematurity (OR=5.0), cesarean section (OR=4.8), placenta previa (OR=22.0), twin pregnancy (OR=6.6), HELLP syndrome (OR=17.9) and severe small-for-gestational-age infants (OR=2.0). The first four were also associated with MNM. CONCLUSION: MNM cases of PPH rates were steady in Burgundy while rates of PPH with transfusion increased moderately.