323,311 research outputs found
The potential role of dual mechanistic opioids in combating opioid misuse
No full textPurpose: In the last years, the consumption of opioid analgesics in western countries, particularly in USA, has dramatically increased, and this rise has been paralleled by a proportional number of opioid-related deaths. To response to this health crisis, opioid guidelines have been developed to reduce the risk of harm related to opioid prescribing. Many activities have been suggested to face opioid epidemic. Clinicians should find a proper balance that meets the patient’s need for pain relief while minimizing abuse. The aim of this review was to examine the value of so-called dual opioids in this context Recent Findings: Many activities have been suggested to face opioid epidemic. Clinicians should find a proper balance that meets the patient’s need for pain relief while minimizing abuse. Dual mechanistic opioids, including tramadol and tapentadol, could be less appealing for opioid abusers, because of the reduced mu-load. Significant differences have been observed in post-marketing surveillance between tramadol and tapentadol, in favor of the latter. Summary: Further investigations are warranted for clarifying the role of innovative molecules for preventing opioid abuse
PLASMA RISORSA STRATEGICA:PROGRAMMA DI PLASMAFERESI E AUTOSUFFICIENZA IN PLASMADERIVATI
No full textVI Conferenza Nazionale dei Servizi Trasfusionali Relazioni Conferenza
RE01
PLASMA RISORSA STRATEGICA:
PROGRAMMI DI PLASMAFERESI
E AUTOSUFFICIENZA IN PLASMADERIVATI
Berti P.(1), Coluzzi S.(2)
(1)SIMT Azienda USL, Aosta; (2) SIMT Policlinico "Umberto I", Roma
Premessa. La raccolta e la conservazione di plasma per la produzione di plasmaderivati hanno assunto negli ultimi anni sempre maggior rilevanza, e sono soggette a stringenti normative di matrice europea che hanno indotto il sistema trasfusionale a importanti processi di adeguamento. Nell'affrontare il problema dell'autosufficienza dei farmaci plasmaderivati non è del resto possibile ignorare che, in aggiunta a tutti i processi riguardanti l'attività di raccolta di plasma, va certamente affrontato anche il problema dell'appropriatezza del loro utilizzo, considerati i dati di consumo italiani che si pongono a livelli disallineati con quelli degli altri paesi avanzati.
Metodi. La survey con 11 domande a risposta multipla inviate a 232 Strutture Trasfusionali (ST) si è proposta di indagare alcuni aspetti critici riguardanti queste attività, con lo scopo di chiarire le interconnessioni fra la pianificazione della raccolta, l'utilizzo clinico del plasma e dei plasmaderivati e il monitoraggio dell'appropriatezza d'uso.
Risultati. Globalmente hanno risposto alla survey 179 (77,2%) ST. In 144 ST (80,4%) viene raccolto plasma mediante aferesi: le procedure eseguite in media per struttura sono lievemente diminuite dal 2015 (n=1.203) al 2017 (n=1.065), così come la produzione (kg medi: da 786 a 747 per struttura).
L'impiego del plasma per uso clinico nelle Strutture Sanitarie avviene in base a Linee Guida/Raccomandazioni condivise con il COBUS nell'88,7% dei casi, ma permane una parte non irrilevante (11,3%) di strutture rispondenti nelle quali esse non sono state definite.
La misurazione della percentuale di richieste di plasma inappropriate non viene eseguita nel 13,9% delle strutture; in quelle ove viene eseguita, l'appropriatezza è elevata (>75% delle richieste) nel 61,5% dei casi.
Riguardo alla tendenza ad assegnare plasma prescindendo da valutazioni contestuali di appropriatezza, ma secondo formule prestabilite, essa viene riferita nel 43,6% dei casi di trasfusione massiva, mentre nel 28,5% mancano protocolli definiti.
Viene segnalata dal 46% delle strutture la necessità di introdurre adeguamenti procedurali e nella selezione del donatore per rispettare i nuovi requisiti di volume della raccolta in aferesi introdotti dal DM 02/11/2015.
Nella definizione del fabbisogno dei farmaci plasmaderivati, che nel 79,9% dei casi vengono forniti dalle Farmacie Ospedaliere e non dalla ST, vi è stato un coinvolgimento dell'azienda nel 63,4% dei casi. Il monitoraggio sul loro impiego clinico (tipo, quantità, indicazioni) vede coinvolto il SIMT solo nel 30,7% dei casi, ma i risultati del monitoraggio sull'impiego clinico dei farmaci plasmaderivati sono accessibili anche alla ST nei casi in cui essa, come avviene nella maggioranza dei casi (55,1%), non ne autorizzi direttamente l'impiego.
Conclusioni. La survey ha evidenziato che la gestione sia dei programmi di plasmaferesi sia del monitoraggio dell'appropriatezza dei farmaci plasmaderivati è alquanto disomogenea. Seppur un'ampia maggioranza di ST (80,4%) effettui procedure di plasmaferesi e mostri di essere coinvolta nei programmi di autosufficienza in farmaci plasmaderivati,
meno evidente risulta il coinvolgimento nel monitoraggio dell'appropriatezza per quanto riguarda i medicinali plasmaderivati, che in larga parte vengono gestiti dalle farmacie ospedaliere.
Elaborazione statistica a cura di Ilaria Ardoino
Degradation of silicon carbide reflective surfaces in the LEO environment
No full textSpace mirrors in Low Earth Orbit (LEO) encounter a degradation problem caused by the impact of atomic oxygen (ATOX) in the space environment. This paper presents an experiment of the atomic oxygen impact degradation and UV synergic effects on ground simulation. The experiment was carried out in a dedicated ATOX simulation vacuum chamber. As target materials, a polished CVD Beta-silicon carbide (SIC) coating was investigated. The selection of silicon carbide is due to its high potential candidate as a mirror layer substrate material for its good reflectance at UV wavelengths and excellent thermal diffusivity. It has highly desirable mechanical and thermal properties and can achieve an excellent surface finish.
The deposition of the coatings were on carbon-based material substrate; i.e., silicon impregnated carbon fiber composite (C/SiC). Mechanical and thermal properties of the coatings such as hardness and Coefficient of Thermal Expansion (CTE) were achieved. Several atomic oxygen impact angles were studied tilting the target samples respect to the flux direction. The various impact angles permitted to analyze the different erosion rates and typologies which the mirrors would encounter in LEO environment.
The degradation was analyzed in various aspects. Macroscopic mass loss per unit area, surface roughness and morphology change were basically analyzed. The exposed surfaces of the materials were observed through a Scanning Electron Microscope (SEM). Secondly, optical diagnostic of the surfaces were performed in order to investigate their variation in optical properties as the evaluation of reflectance degradation. The presence of micro-cracks caused by shrinkage, grinding, polishing or thermal cycling and the porosity in the coatings, could have led to the undercutting phenomenon. Observation of uprising of undercutting was also conducted. Remarks are given regarding capabilities in short-term mission exposures to the LEO environment of this coating
The effect of opiates on bone formation and bone healing
No full textPurpose of Review: Opioids have been shown to be associated with an increased risk of fracture. The purpose of this paper is to review recent research into the effects of opioids on bone formation and bone healing in animal models and in human studies. Recent Findings: Most opioids, such as morphine and fentanyl, negatively affected bone remodeling and bone healing in animal models. Conversely, remifentanil has been recently shown to promote in vitro osteoblast differentiation and to inhibit differentiation and maturation of osteoclasts, therefore reducing bone resorption. According to the possible negative role of opioids in bone healing, opioid antagonists have been shown to enhance bone mineralization, suggesting a possible therapeutic role in the future for osteoporosis. Other neuropeptides, such as the vasoactive intestinal peptide (VIP) and the neuropeptide Y (NPY), have been proved to promote osteogenesis. The increased risk of fractures among opioid users may be related to their central nervous system side effects or to the reduced bone density, partly due to their endocrine effects, and partly to their direct activity on bone cells. Clinical data strongly suggested a potential negative effect of opioids in bone healing. The risk of nonunion fracture is significantly increased in opioid users, and bone mass density was reduced in patients under long-term opioid treatment. Summary: The direct effects of opioids on bone remodeling appears evident from these reports. Not all opioids have the same potential for negatively impacting bone healing. Opioid antagonists may increase bone density and could represent a possible future treatment for low bone mass density pathologies. However, further trials are warranted to clarify the clinical relevance of these emerging findings from animal studies
Naldemedine. A new option for OIBD
No full textOpioid-induced bowel dysfunction (OIBD) is a common complication in long-term opioid users and abusers. It is a burdensome condition, which significantly limits quality of life and is associated with increasing health costs. OIBD affects up to 60% of patients with chronic non-cancer pain and over 80% of patients suffering from cancer pain and is one of the conditions of the most common symptoms associated with opioid main-tenance. Given the continued use of opioids for chronic pain management in appropriate patients, OIBD is likely to persist in clinical practice in the coming years. We will herein review its underlying pathophysiological mechanisms and the available treatments. In the last years, pharmaceutical research has focused on the opportunity of targeting peripheral mu-opioid receptors without affecting their analgesic activity in the central nervous system, and several peripherally acting mu-opioid receptors antagonists (PAMORAs) drugs have been approved. We will mainly focus on naldemedine, discussing its pharmacological properties, its clinical efficacy and side effects. Head-to-head comparisons between naldemedine and the other PAMORAs are not available yet, but some considerations will be discussed based on the pharmacological and clinical data. As a whole, the available data suggest that naldeme-dine is a valid treatment option for OIBD, as it is a well-tolerated drug that alleviates constipation without affecting analgesia or causing symptoms of opioid withdrawal
ANEMIA EMOLITICA AUTOIMMUNE E GRAVIDANZA
No full textANEMIA EMOLITICA AUTOIMMUNE
E GRAVIDANZA
Coluzzi S.(1), Giovannetti G.(1), La Rocca U.(1), Neri A.(1), Santilio I.(1), Girelli G.(1), Arista M.C.(1)
(1)UOC Immunoematologia e Medicina Trasfusionale, Azienda Ospedaliero-Universitaria Policlinico Umberto I, Roma
Premessa. La malattia emolitica autoimmune (MEA) è una condizione acquisita rara causata da anticorpi (Ac) rivolti verso antigeni self eritrocitari. La presenza di autoimmunizzazione eritrocitaria pre-esistente o l'insorgenza durante la gravidanza sono oggetto di attento monitoraggio immunoematologico, in particolare nei casi in cui l'autoAc sia di classe IgG, pertanto in grado di superare la barriera placentare e potenzialmente causare sensibilizzazione degli eritrociti fetali.
Metodi. Sono state revisionate le schede del workup immunoematologico di donne in gravidanza pervenute in un anno nel nostro ambulatorio per il monitoraggio finalizzato alla prevenzione della malattia emolitica feto-neonatale (MEFN); nella maggior parte dei casi si trattava di donne con ricerca Ac risultata positiva presso altri laboratori. In accordo con quanto previsto dalle Raccomandazioni SIMTI-SIGO, è stata effettuata una determinazione del fenotipo ABO/Rh/K nel I trimestre di gravidanza, confermata a 28 settimane di gestazione, e la ricerca di Ac eritrocitari irregolari. In caso di risultato positivo, lo studio includeva: test dell'antiglobulina diretto (TAD), caratterizzazione della classe Ig dell'autoAc ed identificazione di eventuali alloAC, titolazione Ac(auto/ alloAc), come parte del check-up finalizzato all'inquadramento di un'eventuale insorgenza di MEFN e nell'eventualità di una richiesta trasfusionale nella madre e/o nel figlio. Il monitoraggio immunoematologico è stato condotto, in relazione ai risultati ottenuti, secondo quanto previsto dalle Raccomandazioni. Risultati. Nel corso di un anno sono stati effettuati 375 studi immunoematologici in 124 donne in gravidanza. Di queste, in 10 lo studio dava esito negativo, in 3 era evidenziata interferenza dovuta ad Ac verso mezzi potenzianti/conservanti dei pannelli eritrocitari, mentre in 111 lo studio risultava positivo per la presenza di auto o alloAc; in 10/111 pazienti (9%) veniva diagnosticata una MEA (8 da Ac di tipo caldo IgG, 1 di tipo freddo IgM, 1 di tipo misto IgG+IgM). In4/10 pazienti si associavano alloAc (4 casi anti-Wra, 1 anti-Wra+anti-E (titolo1), 1 anti-C (indosabile); il titolo dell'autoAc IgG era<16 in tutti i casi. In 3/10 neonati da madri con autoimmunizzazione eritrocitaria, il TAD alla nascita era risultato positivo, di tipo IgG, e si eluiva l'Ac privo di specificità convenzionali, di provenienza materna; nessuno dei tre neonati con TAD positivo aveva presentato anemia e/o iperbilirubinemia alla nascita e al controllo a 1 mese.
Conclusioni Nella nostra esperienza il riscontro di autoAc materni non ha comportato alcuna conseguenza nel feto/ neonato; tuttavia in tutti i casi il titolo degli autoAc era modesto, anche nei casi in cui era stato necessario instaurare terapia steroidea nella madre a causa della significatività clinica dell'autoAc. Seppur anche in letteratura sia riportata una bassa percentuale di neonati con segni di emolisi causati da autoAc materni, cionondimeno è raccomandato un atteggiamento di attenta sorveglianza, al fine di instaurare un pronto trattamento nella madre, soprattutto nei casi in cui si associ un più ampio disordine dell'immunità, e per evidenziare alloAc che, eventualmente presenti e più pericolosi per il feto, potrebbero essere mascherati dall'autoAc
ESAME EMOCROMOCITOMETRICO COME TEST DI VALUTAZIONE CLINICA DEL DONATORE
No full textLe attuali normative in merito alle attività di medicina trasfusionale ribadiscono il ruolo della tutela della salute dei donatori, garantito anche attraverso l’effettuazione regolare di esami di laboratorio, al fine di assicurare un elevato livello di protezione della salute umana. Anche se non previsto tra gli esami per la validazione biologica degli emocomponenti, l’esame emocromocitometrico rientra tra gli esami obbligatori ad ogni donazione; d’altra parte le linee guida nazionali e comunitarie richiedono che gli emocomponenti soddisfino requisiti di qualità, strettamente connessi con le caratteristiche del donatore e condizionanti l’efficacia della terapia trasfusionale nel ricevente. L’esame emocromocitometrico rappresenta senza dubbio l’indagine da richiedere in prima istanza per verificare lo stato di salute di un individuo e rappresenta sicuramente un criterio di protezione del donatore di sangue, consentendo da un lato di evidenziare precocemente le manifestazioni di effetti collaterali connessi alla periodicità del dono, dall’altro potendo rappresentare la spia di un eventuale danno ematologico primitivo o secondario a patologie di organi o apparati extra-emopoietici. Uno dei principali effetti collaterali della donazione di sangue è rappresentato dall’insorgenza di alterazioni del metabolismo del ferro, dal momento che la perdita di 200 mL di eritrociti con una donazione di sangue intero comporta la perdita di circa 225 mg di ferro. In condizioni di compenso delle perdite marziali e di una normale funzionalità dei meccanismi fisiologici di risposta all’ipossia, il sistema ematopoietico riesce a rigenerare un normale contenuto di emoglobina. Tuttavia, in condizioni di bilancio marziale in equilibrio instabile, come nel caso di donne in età fertile o anche in
donatori di sesso maschile in relazione alla frequenza delle donazioni, la concentrazione di emoglobina nel sangue può progressivamente ridursi.
La determinazione dell’emoglobina, obbligatoria in fase di selezione del donatore, è stata giustamente considerata dal legislatore determinante per il giudizio di idoneità del donatore. Tuttavia succede che individui con valori di emoglobina anche superiori rispetto ai limiti stabiliti presentino una carenza marziale latente ed è dovere del medico di medicina trasfusionale intervenire, dal momento che “possono sussistere motivi per i quali è necessario, ai fini della protezione della salute del candidato donatore, rinviare la donazione” (Allegato, 3 DM 3 Marzo 2005). In questo contesto la sola determinazione dell’emoglobina è inadeguata nell’evidenziare precocemente condizioni carenziali mentre maggiori informazioni possono essere fornite da altri parametri emocromocitometrici (MCV, MCH, MCHC, RDW). Inoltre problemi di natura etica sorgono sia in caso di carenza di ferro legata alle frequenti donazioni, sia nel caso, meno frequente ma più grave, in cui la carenza marziale sia legata a patologie ancora asintomatiche. Altri parametri forniti dall’emocromo possono segnalare condizioni che impongono l’esclusione, anche solo temporanea, del donatore: alterazione dei leucociti e delle popolazioni leucocitarie o della conta piastrinica potrebbero essere associate a patologie infettive, ematologiche o immunologiche, meritevoli di maggiori approfondimenti diagnostici. Pertanto è auspicabile che il processo di arruolamento del donatore di sangue ed emocomponenti preveda l’esecuzione di un esame emocromocitometrico preliminarmente alla donazione, al fine della tutela dello stesso donatore dall’effettuazione di una donazione in condizioni di salute non sempre ottimali che impongono, in fase di validazione, l’eliminazione dell’unità donata a causa di alterazioni anche importanti di parametri emometrici
Using opioid therapy for pain in clinically challenging situations. Questions for clinicians
No full textHealthcare professionals and organizations increasingly face the conundrum of treating patients with active substance use disorder, a history of personal or familial substance use disorder, or those at elevated risk for substance abuse. Such patients need compassionate care when facing painful conditions; in fact, denying them pain control makes it likely that they will seek out ways to self-medicate with illicit drugs. Yet it remains unclear how to safely and effectively treat patients in these challenging situations. The authors have formulated ten questions to address in order to provide adequate analgesia for such patients. These questions demand a highly individualized approach to analgesia. These ten questions involve understanding the painful condition (presumed trajectory, duration, type of pain), using validated metrics such as risk assessment tools, guidelines, protocols, and safeguards within the system, selection of the optimal analgesic product(s) or combination therapy, and never starting opioid therapy without clear treatment objectives and a definitive exit plan. It is tempting but inaccurate to label these individuals as “inappropriate patients,” rather they are high-risk individuals in very challenging clinical situations. The challenge is that both options — being in pain or being treated with opioids to control pain — expose the patient to a risk of rekindling an addiction. The question is how do we, as clinicians, adequately respond to these very perplexing clinical challenges
Alcune proprietà dei movimenti del Piano Ellittico e del Piano Iperbolico costruiti su una quadrica a punti ellittici
No full textRecommendations for the prevention and treatment of haemolytic disease of the foetus and newborn
No full textRecommendations for the prevention and treatment of haemolytic disease of the foetus and newborn
Francesco Bennardello,1 Serelina Coluzzi,2 Giuseppe Curciarello,3 Tullia Todros,4 and Stefania Villa5, as Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) and Italian Society of Gynaecology and Obstetrics (SIGO) working group
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Introduction
The publication of the second edition of the “Recommendations for the prevention and treatment of haemolytic disease of the foetus and newborn” is the result of collaboration between the Italian Society of Transfusion Medicine and Immunohaematology (SIMTI, Società Italiana di Medicina Trasfusionale e Immunoematologia) and the Italian Society of Gynaecology and Obstetrics (SIGO, Società Italiana di Ginecologia e Ostetricia).
The recommendations published in 20061 have been revised in the light of current scientific evidence: the immunohaematological and instrumental investigations that should be performed in the antenatal and perinatal periods, the immunoprophylaxis (IP) to prevent the haemolytic disease of the foetus and newborn (HDFN due to RhD incompatibility and the treatment to use if HDFN develops are described.
The recommendations are focused on the prevention and management of HDFN, in particular that one due to RhD incompatibility, the most serious form of this condition. Although IP has dramatically reduced the number of cases of HDFN, this disease continues to occur and engage specialists in Transfusion Medicine, Obstetrics and Neonatology. The recommendations are aimed at Transfusion Structures (TS) and all public facilities pertaining to Mother and Child Departments, Family Planning Clinics and private structures managing pregnancies, including those in which the woman gives birth at home. The prevention of HDFN must be guaranteed, through organisational models adapted to local circumstances, to all pregnant women for whom it is deemed necessary and the women must also be ensured adequate information.
Besides HDFN due to RhD incompatibility, the recommendations also cover less frequent forms of the disease, caused by immunisation to other blood group antigens, and by ABO incompatibility, which is a more frequent laboratory finding, although of less importance from a clinical point of view.
These recommendations will be periodically reviewed in the light of evolving scientific knowledge, technology and clinical practice. They were developed on the basis of an analysis of current scientific literature (identified through bibliographic searches of Medline/PubMed and Ovid databases) and were submitted to the consensus of experts from SIMTI and SIGO. Protocols jointly agreed upon by the Transfusion Medicine and Immunohaematology Services (SIMT, Servizio di Immunoematologia e Medicina Trasfusionale) and Obstetricians-Gynaecologists working in the same territory, including at a regional level, should be drawn up to promote compliance among pregnant women.
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Purpose of the recommendations
The purpose of this document is to give correct guidance on the management and prevention of HDFN with the aim of promoting homogeneous practices throughout Italy, ensuring a minimum common denominator of quality that can be achieved in all health care structures2 used by pregnant women or females of childbearing potential*.
The dual value of these recommendations is that besides being a technical and scientific support for doctors making clinical decisions regarding the management of HDFN, they also provide updates on the risks associated with immunisation in females of childbearing potential.
The recommendations are not intended in any way to replace either the physician’s clinical evaluation of individual cases or the doctor’s personal experience; they are, rather, a reference tool that can also be used to check the correctness of treatment. The final decision on a given treatment must always be taken by the doctor in the light of the clinical picture and resources available; however, substantial deviations from these recommendations should be documented and justified in the patient’s clinical records. For this purpose specific indicators for monitoring and evaluation have been identified to use in clinical audits.
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Expected benefits
The expected benefits of the dissemination of these recommendations for the prevention and management of HDFN are as follows:
- a decrease in the incidence of HDFN;
- a decrease in the incidence of alloimmunisation;
- an increase in appropriate clinical use of blood components in the foetal and neonatal periods;
- an increase in the appropriate clinical use of blood components in females of childbearing potential;
- an increase in the appropriate clinical use and dosages of anti-D immunoglobulin (Ig);
- greater involvement of patients in decisions related to the prevention and management of HDFN.
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Intended users of the recommendations
Doctors and healthcare workers involved in the prevention, diagnosis and treatment of HDFN.
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Applicability
These recommendations are applicable to females of childbearing potential, pregnant women at risk of HDFN and foetuses/neonates affected by haemolytic disease caused by materno-foetal alloimmunisation.
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Methodology of the Working Group and grades of recommendation
The process of developing these recommendations, in accordance with the indications contained in the methodology manual of the National Guidelines Programme3, was based on systematic reviews of the literature and updating of already existing recommendations on the subject. For most of the recommendations there is an explicit evaluation of the quality of the proof leading to the recommendation and the strength with which the recommendation is made. In the absence of clear proof, the recommendations are based on a consensus of published opinions of experts and that of the Working Group.
The methodology used to derive the grades of recommendation was based on that used by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group4–6. According to the GRADE system, recommendations are classified by grades, expressed in Arabic numbers (1, 2), depending on their strength, and by letters (A, B, C) depending on the quality and type of evidence provided by the studies on which the recommendations are based.
In detail:
- Grade 1: the authors are confident that the benefits for health clearly outweigh the undesirable effects, in terms of both risk and economic cost. This is, therefore, a strong recommendation.
- Grade 2: the authors are less certain and the difference between desirable and undesirable effects is less clear. This is, therefore, a weak recommendation.
As to the quality and type of evidence provided by the studies in support of the recommendations, there are three levels of classification:
- Grade A: high level of evidence.
The evidence derives from the analysis of numerous, substantial randomised studies without major limitations. It is unlikely that further research would alter the conclusions reached by these studies.
- Grade B: moderate level of evidence.
The evidence is derived from randomised clinical trials but with important limitations (for example, inconsistent results, wide confidence intervals, methodological problems). Grade B is also attributed to recommendations derived from strong evidence collected in observational studies or case series (for example, treatment effects or the demonstration of a dose-response effect). Further research could change the conclusions of these studies.
- Grade C: low or very low level of evidence.
The evidence is derived from an analysis of observational clinical studies with less consistent results or from the clinical experience/opinions of experts. Further research is required to consolidate or change the conclusions presented.
Generally speaking, it can be assumed that for all recommendations other than Grade 1A the authors recognise that other interpretations of the available evidence and other “clinical policies” are reasonable.
The conventional classification of evidence is based on mathematical and statistical criteria, with the “strength” of the evidence being assigned, in order, to: meta-analyses, randomised controlled trials, retrospective analyses, prospective follow-ups, cross-sectional population studies, reviews, anecdotal reports. This is correct as far as regards strictly clinical studies, especially if they are investigations of therapies and focused on objective evaluations of outcome.
Nevertheless, the recommendations in some fields are weak; in contrast, in other areas the availability of clinical studies carried out with rigorous methodology in large groups of subjects has enabled specific recommendations to be made with more confidence.
It was not always possible to use aggregate data from meta-analyses: these variables increase the margins for individual decisions by each doctor and for each patient.
As to transfusion support for HDFN in the antenatal and postnatal periods (intrauterine transfusion, exchange transfusion [ET], neonatal transfusion), the fundamental principles taken from the “Recommendations for transfusion therapy in neonatology”7 and subsequent amendments are reported in the appendix.
The appendix also contains some recommendations to be followed in order to avoid the risk of immunisation when transfusing females of childbearing potential, a summary of the investigations to carry out during pregnancy and the puerperium to enable the correct prevention of HDFN, and a flow-chart describing the immunohaematological monitoring of women during pregnancy and at delivery. Finally, the recommendations are summarised and reported with their classification at the end of the appendix.
Each member of the Working Group has signed a statement, which conforms with the one adopted by the National Guidelines Programme, declaring that they have no conflicts of interest3.
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Haemolytic disease of the foetus and newborn due to maternal-foetal RhD incompatibility
The anti-D alloantibody is the antibody most frequently responsible for HDFN8,9. Before the introduction of anti-D IP, HDFN secondary to anti-D immunisation affected 1% of neonates and was the cause of death of one in every 2,200 babies born10. Although the introduction of post-partum IP in RhD negative pregnant women drastically reduced the incidence of cases of HDFN11, HDFN due to anti-D continues to occur in 0.4 of every 1,000 births12–13 and red blood cell alloimmunisation still remains the most common cause of foetal anaemia14. There are various reasons for the continued occurrence of this disease: (i) the possible development of anti-D immunisation during a pregnancy as a result of an occult foetal-maternal haemorrhage (FMH), usually after the 28th week of gestation, which affects about 1% of RhD negative mothers of a RhD positive foetus15; (ii) lack of administration of IP; (iii) ineffective IP because the amount administered was not sufficient for the volume of the FMH; (iv) possible errors in the typing of the pregnant woman, puerpera or neonate; and (v) possible errors in the transfusion treatment of females of childbearing potential (transfusion of red blood cell concentrates with mismatched RhD antigen).
The fundamental cause of HDFN is the reaction between class IgG maternal antibodies and antigens on foetal red blood cells, leading to the destruction of these cells, mainly in the spleen.
HDFN rarely occurs during a first pregnancy, unless the mother has been previously sensitised by transfusions. Usually, during the first pregnancy primary immunisation takes place; this immunisation is characterised by the production of a small amount of IgM antibodies, immunoglobulins which do not cross the placenta. In subsequent pregnancies, and after further exposure to the antigen, as a result of the secondary immunisation, IgG antibodies, which can cross the placenta and cause haemolysis, are produced. The immune response depends on the entity of the FMH, the number of immunising events and the capacity of the woman’s response. ABO incompatibility between mother and foetus partially protects against immunisation.
In the natural history of HDFN, without any kind of intervention, in 50% of cases the foetus has only mild signs of the disease and recovers without any treatment; in 25% of cases the foetus develops haemolysis and kernicterus, if not treated adequately at birth; and in the remaining 20–25% of cases, HDFN due to anti-D may present in its most severe form (hydrops foetalis and death) before the 34th week of gestation16.
However, with the improvement of maternal and foetal monitoring and the current possibility of in utero treatment, the incidence of severe cases (hydrops and death) has now been reduced to about 10.
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Haemolytic disease of the foetus and newborn due to incompatibility for other red blood cell antigens
Besides the RhD antigen, other antigens belonging to the Rh system and other known blood group systems (with the possible exclusion of those of the Lewis, Chido and Rodgers, and Knops systems and of the I/i collection) can also induce the production of IgG antibodies and, therefore, provoke HDFN if a person lacking an antigen comes into contact with that antigen as a result of a pregnancy or transfusion. As a general rule, the forms of HDFN not due to RhD incompatibility are clinically benign, such that only 10% of them are clinically severe enough to require transfusion therapy; nevertheless, there are descriptions of fatal cases in the literature18.
The order of frequency of HDFN, after the forms due to RhD incompatibility and ABO incompatibility, are those caused by incompatibility for the c antigen (r′), the Kell antigen (K1), the C antigen and the antigens of the Duffy system19–20. Still in strict order of frequency, there are the forms of HDFN due to incompatibility for antigens of the Kidd, MNS, and Dombrock systems and others, which are all very rare. Anti-Cw, -Fyb, -Jka, -Jkb, -Jk3, -S, and -s usually only cause a positive direct antiglobulin test (DAT) in the neonate and treatment, if necessary is almost always limited to phototherapy21.
Anti-M, which may also be of the IgG class, rarely cause HDFN. The same applies for warm autoantibodies. Antibodies such as anti-I, -P, -Lea and -Leb can be ignored because the corresponding antigens are scarcely present at birth.
Various studies22–25 have shown that HDFN caused by anti-K differs from that due to anti-D in a number of ways. In women with anti-K, the obstetric history is not usually predictive of the severity of the disease; there is only a weak correlation between antibody titre and the severity of the disease, haemolysis and the consequent hyperbilirubinaemia are not dominant features of the disease and the suppression of foetal erythropoiesis, rather than haemolysis, is the most important pathogenic mechanism in causing foetal anaemia. Pregnancies in which anti-K maternal-foetal alloimmunisation has occurred, even when the antibody titre is low (1:8 or greater), must, therefore, be considered at risk, given the severity of the foetal and/or neonatal clinical manifestations.
The recent increase in migration to Italy has led to the diagnosis of other forms of HDFN due to antigens rarely observed in the Italian population. The search for irregular antibodies in these forms of HDFN is often falsely negative because of the lack of the relevant antigens in the test red cell panels commonly used, which are prepared with red blood cells from Caucasians. In these cases, the alloantibody involved can be detected and identified by using the father’s red cells (if ABO compatible with the mother’ ones), or, after delivery, the neonate’s cells. The protocols regarding investigations to carry out during pregnancy and in the perinatal and postnatal periods, as well as the treatment, are not different from those recommended for HDFN due to RhD incompatibility, to which the reader is referred.
Once an antibody specificity has been identified, the test red cells to use in controls, in determining the titre and in studies of the eluate of neonatal erythrocytes must express the antigen in question. In contrast, the red cells to use for a possible ET or for transfusion into the neonate must not carry the antigen involved.
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Haemolytic disease of the foetus and newborn due to maternal-foetal ABO incompatibility
HDFN due to ABO incompatibility is currently the most common neonatal haemolytic disease in the western world; indeed, in 15–20% of pregnancies in the white population there is incompatibility between a group O mother and a group A or B child; in 10% of these pregnancies, HDFN develops as a result of destruction of the foetal red blood cells, caused by IgG class anti-A and/or anti-B antibodies in the maternal serum. The mother-child serological combination in which a clinically relevant ABO HDFN develops most readily is a group O mother and a group A neonate.
However, only in about 1.5–2% of cases does the haemolytic disease require transfusion support26,27. There are various reasons for the prevailing modest clinical expression of HDFN due to ABO incompatibility:
- the expression of A and B antigens on foetal and neonatal red blood cells is low;
- the A and B substances, ubiquitously present on endothelial and epithelial cells, including placental ones, adsorb some of the maternal IgG that crosses the placenta;
- anti-A and anti-B IgG are predominantly IgG2, a subclass of Ig with a lesser capacity to cross the placental barrier actively.
Nevertheless, there are occasional reports in the literature of severe cases of haemolytic disease that have required ET and complex management28,29.
The incidence of HDFN due to ABO incompatibility is higher in African and Arab populations because of the more frequent expression of A and B genes in these populations. Given the migratory phenomena involving Italy (the 2013 CEDAP report [analysis of Birth Support Certificates] described that, in 2010, 18.3% of births were to women of non-Italian citizenship, with the peak being 28% in the region of Emilia Romagna), it can be predicted that the incidence of this type of HDFN will increase in the future30.
The incidence of HDFN due to ABO incompatibility is the same in first pregnancies as it is in subsequent pregnancies; the disease is, therefore, neither preventable nor predictable.
The search for anti-A and/or anti-B IgG during a pregnancy is of little use for predicting the development of ABO HDFN in the unborn child. In fact, most pregnant women, especially those with group O blood, have anti-A and/or anti-B (and anti-A,B) IgG in their serum, whereas relatively few neonates are affected by haemolytic disease, particularly clinically important forms.
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Investigations during pregnancy to prevent and manage haemolytic disease of the foetus and newborn
Immunohaematological tests to perform in all women (Table I)
Table I
Recommendations on immunohaematological tests to perform in all women.
Rec. n. Recommendation GoR
1 It is recommended that the ABO group and RhD factor are determined and a search for irregular antibodies is carried out with an IAT in all pregnant women, independently of their RhD status, within the first trimester of pregnancy in a Transfusion Structure. 1B
2 It is suggested that the samples for immunohaematological investigations are identified as samples for pre-transfusion tests and carry the surname, name and date of birth of the patient and the signature of the person who took the sample. 2C
3 It is suggested that all pregnant women are notified of their RhD status because of the possible need for prophylaxis with anti-D Ig. 2B
4 It is suggested that the search for irregular antibodies is repeated in all pregnant women at 28 weeks of gestation, regardless of their RhD status. In RhD negative women receiving antenatal prophylaxis at 28 weeks of gestation, the IAT should be performed before the IP is administered. 2B
5 If the search for antibodies is positive, for the purpose of evaluating the risk of HDFN, it is suggested that the specificity, titre and origin of the antibodies are determined and that a careful immunohaematological and obstetric history of the woman is taken. 2B
6 It is suggested that RhD typing and screening and identification of irregular antibodies is performed using methods in line with those set out in the SIMTI Standards. 2C
7 It is recommended that anti-A and anti-B immune antibodies are not searched for or monitored in pregnant women. 2B
- ABO blood group and RhD factor must be determined in all pregnant women, preferably within the first trimester of pregnancy. The tests must be performed in a TS using validated methods9,31–32.
- Samples of blood from pregnant women must carry the surname, name and date of birth of the patient and the signature of the person who took the sample33,34. The patient’s personal data must be transcribed in the presence of the patient herself, who must confirm the data.
- Two different monoclonal anti-D reagents, which must not recognise the DVI variant of the RhD antigen, must be used to determine the RhD type32,33. Determination of weak D antigen is not recommended since this is not useful and could lead to a dangerous omission of IP in the absence of in depth investigations, which cannot be carried out in all immunohaematology laboratories.
- All pregnant RhD negative women should be giv
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