Practices for RhD alloimmunization prevention: a vignette-based survey of midwives.

INTRODUCTION: Despite the availability guidelines to prevent RhD alloimmunization, severe hemolytic disease of fetus and newborn still occurs in high-income countries. The aim of the study was (1) To assess variations in practices for the prevention of RhD alloimmunization, and (2) to understand midwives' acceptance and appropriation of fetal RhD genotyping. METHODS: Descriptive cross-sectional survey of French midwives from September 2017 through January 2018. Participants were asked to complete an internet-based questionnaire that included three clinical vignettes. They were questioned about their practices concerning early pregnancy visit by RhD-negative women, prevention of RhD alloimmunization in women with second-trimester metrorrhagia, and RhD fetal genotyping. RESULTS: A total of 827 midwives completed the questionnaire. Only 21.1% reported that they practice all the preventive measures recommended in early pregnancy. In a situation at high risk of RhD alloimmunization during pregnancy, 97.2% of midwives would perform immunoprophylaxis. Nearly, all midwives reported providing information about RhD alloimmunization (92.4%) at the beginning of pregnancy, although only 11.3% offered both written and verbal information; at the time of systematic anti-D immunoprophylaxis (28 weeks), 78% provided information, but only 2.7% both verbally and in writing. Finally, only 50.8% of midwives preferred to include RhD fetal genotyping in routine prenatal prophylaxis. DISCUSSION: This study showed significant variations in French midwives' practices to prevent RhD alloimmunization. Better dissemination of guidelines is needed to improve both consistent use of these practices and the quality of information delivered to RhD-negative pregnant women.

RhIg for the prevention Rh immunization and IVIg for the treatment of affected neonates.

Rhesus D (RhD) negative pregnant women carrying an RhD positive fetus are at risk of developing anti-D during or after pregnancy. Anti-d-immunoglobulin (RhIg), which is mainly produced from special plasma donated in a few countries for the whole world, is able to prevent an anti-D alloimmunization. Through the introduction of ante- and postnatal anti-d-prophylaxis into clinical routine, the frequency of hemolytic disease of fetus and newborn decreased considerably. Postnatal prophylaxis from the beginning in the 1960s has been applied only to women who delivered an RhD positive newborn. Because the fetal RhD status can be determined with high sensitivity and accuracy from the mother's peripheral blood, targeted antenatal anti-d-prophylaxis is becoming a new standard procedure in more and more countries. Phototherapy and exchange transfusion are still the main pillars for the treatment of RhD hemolytic disease of the newborn. The efficacy of IVIg in the management of these neonates is not conclusive and cannot be recommended until a larger randomized, double-blind, placebo-controlled study is performed.

Rh Alloimmunisation: Current Updates in Antenatal and Postnatal Management.

In spite of advances in medical science, Rh alloimmunisation remains one of the leading causes of preventable neuro-morbidities and significant neonatal hyperbilirubinemia in lower-middle income countries. Despite availability of effective antenatal preventive strategy (Anti-D), its uptake in antenatal period is low due to ignorance. Further, once diagnosed, there is lack of adequate antenatal follow up in health care facility. Some of these cases even remain undiagnosed in antenatal period only to present as a case of severe hyperbilirubinemia and kernicterus in late neonatal period. Thus, there is an urgent need for creating awareness and educating health care professionals for early detection and timely management in both antenatal and postnatal period. Following two doses of anti-D prophylaxis (one in antenatal period and one in immediate postnatal period) the incidence of Rh alloimmunisation can reduce to <1%. It is recommended to follow all Rh alloimmunised pregnancies antenatally with serial indirect Coombs test titre (till critical titre is reached) followed by serial Doppler velocimetry of middle cerebral artery in a perinatal centre where facility for intrauterine transfusion as well as advanced neonatal care is available. Postnatal management of these infants comprises of confirmation of diagnosis, aggressive phototherapy and in selective cases, double volume exchange transfusion. With appropriate antenatal and postnatal management, the prognosis of Rh alloimmunised pregnancy remains favourable and long term outcome of Rh alloimmunised infants remain comparable with their normal counterparts.

Mitigation strategies for anti-D alloimmunization by platelet transfusion in haematopoietic stem cell transplant patients: a survey of NCCN® centres.

BACKGROUND AND OBJECTIVES: D-negative patients are at risk of developing an alloantibody to D (anti-D) if exposed to D during transfusion. The presence of anti-D can lead to haemolytic transfusion reactions and haemolytic disease of the newborn. Anti-D alloimmunization can also complicate allogeneic haematopoietic stem cell transplantation (HSCT) with haemolysis and increased transfusion requirements. The goal of this study was to determine whether cancer centres have transfusion practices intended to prevent anti-D alloimmunization with special attention in patients considered for HSCT. METHODS AND MATERIALS: To understand transfusion practices regarding D-positive platelets in D-negative patients with large transfusion needs, we surveyed the 28 cancer centres that are members of the National Comprehensive Cancer Network® (NCCN® ). RESULTS: Nineteen centres responded (68%). Most centres (79%) avoid transfusing D-positive platelets to RhD-negative patients when possible. Four centres (21%) avoid D-positive platelets only in D-negative women of childbearing age. If a D-negative patient receives a D-positive platelet transfusion, 53% of centres would consider treating with Rh immune globulin (RhIg) to prevent alloimmunization in women of childbearing age. Only one centre also gives RhIg to all D-negative patients who are HSCT candidates including adult men and women of no childbearing age. CONCLUSION: There is wide variation in platelet transfusion practices for supporting D-negative patients. The majority of centres do not have D-positive platelet transfusion policies focused on preventing anti-D alloimmunization specifically in patients undergoing HSCT. Multicentre, longitudinal studies are needed to understand the clinical implications of anti-D alloimmunization in HSCT patients.

Rhesus D alloimmunization in pregnancy from 1996 to 2015 in Iceland: a nation-wide population study prior to routine antenatal anti-D prophylaxis.

BACKGROUND: Rhesus D (RhD) incompatibility is still the most important cause of hemolytic disease of the fetus and newborn (HDFN) worldwide. The aim of this study was to investigate the incidence, causes, and consequences of anti-D alloimmunizations in pregnancy in Iceland, prior to implementation of targeted routine antenatal anti-D prophylaxis (RAADP) in 2018. STUDY DESIGN AND METHODS: This was a nation-wide cohort study of 130 pregnancies affected by RhD alloimmunization in Iceland in the period from 1996 through 2015. Data were collected from transfusion medicine databases, medical records, and the Icelandic Medical Birth Register. RESULTS: Of 130 RhD alloimmunizations, 80 cases (61.5%) represented new RhD immunization in the current pregnancy. Sensitization was discovered in the third trimester in 41 (51.3%) and occurred in the first pregnancy in 14 cases (17.5%). The most likely causative immunization event was the index pregnancy for 45 (56.25%), a previous pregnancy/birth for 26 (32.5%), abortion for 3 (3.75%), and unknown for 6 women (7.5%). Higher anti-D titers were associated with shorter gestational length, cesarean sections, positive direct antiglobulin test (DAT), and severe HDFN. Intrauterine transfusion (IUT) was performed in five pregnancies (3.8%), and 35 of 132 (26.5%) live-born neonates received treatment for HDFN; 32 received phototherapy (24.2%), 13 exchange transfusion (9.8%), and seven simple blood transfusion (5.3%). CONCLUSION: In about half of cases, RhD alloimmunization was caused by the index pregnancy and discovered in the third trimester. Thus, the newly implemented RAADP protocol should be effective in reducing the incidence of RhD immunization in Iceland in the future.

Targeted antenatal anti-D prophylaxis program for RhD-negative pregnant women - outcome of the first two years of a national program in Finland.

INTRODUCTION: The aim of this study was to assess the accuracy of the non-invasive fetal RHD test at 24-26 weeks of gestation as part of the national antenatal screening program to target routine antenatal anti-D prophylaxis (RAADP) at 28-30 weeks at women carrying an RhD-positive fetus. MATERIAL AND METHODS: A prospective cohort study involving all maternity care centers and delivery hospitals in Finland between February 2014 and January 2016. Fetal RHD genotyping using cell-free fetal DNA in maternal plasma was performed with real-time polymerase chain reaction in a centralized setting. The results were systematically compared with the serological newborn RhD typing. The main outcome measure was the accuracy of the fetal RHD assay; the secondary variable was compliance with the newly introduced RAADP program. RESULTS: Fetal RHD was screened from 10 814 women. For the detection of fetal RHD, sensitivity was 99.99% [95% confidence interval (CI) 99.92-99.99] and specificity 99.81% (95% CI 99.60-99.92). One false-negative and seven false-positive results were reported by the delivery hospitals in two years. The negative predictive value of the test was 99.97% (95% CI 99.81-99.99). At the end of the study period, over 98% of the RhD-negative women participated in the new screening program. CONCLUSIONS: The targeted RAAPD program was implemented effectively in the national maternity care program in Finland. An accurate fetal RHD screening test allows discontinuation of newborn testing without risking the postnatal prophylaxis program. In the future, the main area to investigate will be the clinical effect of RAADP on subsequent pregnancies.

Routine testing of fetal Rhesus D status in Rhesus D negative women using cell-free fetal DNA: an investigation into the preferences and information needs of women.

OBJECTIVE: The goal of this study is to investigate women's preferences and information needs for routine implementation of fetal Rhesus D (RhD) typing using cell-free fetal DNA. METHODS: A questionnaire was developed following focus groups and interviews with both health professionals and RhD negative (RhD-) women offered fetal RhD genotyping within a research study and distributed to RhD- women attending routine antenatal appointments in four National Health Service hospitals. Current knowledge of blood types, anti-D administration, fetal RhD genotyping and future practices were explored. RESULTS: A total of 19 respondents participated in interviews and focus groups, and 270 respondents completed the questionnaires. Questionnaire respondents overwhelmingly felt that the test should be offered to all RhD- women (92.1%), and 75.9% said that they would accept this test. Most were happy to have the test even if it involved extra blood tests (89.3%) or appointments (79%). The knowledge of blood groups was poor. Although 90.7% knew that the baby could have a different blood group from themselves, only 34% knew that blood groups are inherited from both parents. More than 40% were not aware that anti-D would not be required if their baby was RhD-. CONCLUSIONS: Women would welcome the introduction of routine fetal RhD genotyping. Information leaflets and training of midwives will be essential for implementation to ensure good understanding regarding testing.

Has anti-D prophylaxis increased the rate of positive direct antiglobulin test results and can the direct antiglobulin test predict need for phototherapy in Rh/ABO incompatibility?

AIM: To determine the impact of Rhesus (Rh) D prophylaxis on positive direct antiglobulin test (DAT) results and ability of a DAT grade to predict an infant's need for phototherapy. METHODS: Laboratory and infant medical records were reviewed for DAT status, DAT grade, interventions for hyperbilirubinemia including phototherapy, blood transfusion, exchange transfusion and intravenous immunoglobulin. Two epochs of DAT results were reviewed, the first in the era prior to Rh D prophylaxis, the second after introduction of standardised Rh D prophylaxis for Rh negative women. RESULTS: A total of 165 DAT-positive infants' medical records were reviewed. The number of positive DAT results increased from 1.5% to 2.3% (P < 0.0001) following introduction of anti-Rh D prophylaxis, the increase related to an increase in anti-D DATs (7.4% to 32% -P < 0.0001). An infant with a DAT grade of 5-8 was 2.6 times more likely to need phototherapy than an infant with a DAT grade of 2-4 (odds ratio (OR), 2.571; 95% confidence interval (CI), 1.225-5.393; P = 0.08) and an infant with a DAT grade of 10-12 was 4.7 times more likely to need phototherapy than an infant with a DAT grade of 2-4 (OR, 4.724; 95% CI, 1.602-13.926, P =0.013). CONCLUSIONS: Rh D prophylaxis has increased positive DAT results, which may increase the number of unnecessary bilirubin measurements. A low or high DAT grade is strongly predictive of whether an infant does or does not require phototherapy. However, an intermediate DAT requires concomitant bilirubin measurements to determine phototherapy requirements.

Update on the management of non-anti D antibodies.

With the development of the Rh D immunoglobulin and utilisation in clinical practice, severe rhesus iso-immunisation is rarely seen today. Antibodies against other blood groups are now more common than anti-D and while the majority do not cause significant haemolysis, there are reports of serious morbidity with antibodies other than anti-D. We reviewed retrospectively all cases (excluding anti-D and anti kell antibodies) where antibodies were detected at routine booking visit between 1997-2001 and correlated the type of antibody to clinical outcome as assessed by coombs test, postnatal phototherapy and transfusion. Our approach to these cases does not involve invasive test as amniocentesis and relies on the ultrasound monitoring, level of antibodies and timely delivery with appropriate paediatric follow up. Over five years period 150 women were identified with antibodies other than anti-D or anti-kell. There were no directly related deaths. Many authorities suggest amniocentesis for specific antibodies to assess fetal haemolysis and plan management. This study support a non-invasive approach with mortality and minimal morbidity.

[Foetomaternal erythrocyte incompatibilities: from immunohaematologic surveillance of pregnant women to haemolytic disease of the newborn]. / Incompatibilités foetomaternelles érythrocytaires (IFME): de la surveillance immunohématologique des femmes enceintes à la maladie hémolytique du nouveau-né (MHNN).

Despite the generalization of prevention measures against foetomaternal alloimmunization with anti-D immunoprophylaxis since 1970s, retrospectively 30 years later, its complications (new-born child's severe haemolytic disease, foetal death by anemia or nuclear icterus by bilirubin encephalopathy) have not disappeared. At the same time, alloimmunizations against antigens other than D increase with no possible prevention. As part of the set up in France of regional files analysing and making an inventory of serious foetomaternal incompatibilities requiring in utero or neonatal transfusion, we felt the need to synthesize current data, biological profiles (early screening of erythrocytic alloimmunization and its follow up during pregnancy, father's immunohaematologic status, evaluation of in utero immune haemolysis and impact of new non invasive techniques of diagnosis-RH1 foetal genotypage from ADN foetal of RH1--mothers' maternal plasma), clinical and paraclinical data (evaluation of foetal haemolysis by echography, recording of foetal movements and foetal cardiac rhythm), therapeutic indicators (in utero foetal transfusions or exsanguinotransfusions, neo and postnatal transfusions or exsanguinotransfusions, induced premature labour, newborn's intensive continue phototherapy and Rhesus immunoprophylaxis) in order to enable medical and paramedical professionals to carry out the specific supervision of pregnancies with foetomaternal incompatibility, the in utero, neo- and postnatal treatment of child and the efficient therapeutic prevention of anti-D alloimmunization, in a cooperative way.

An audit of the investigation and use of anti-D immunoglobulin prophylaxis in Tayside.

OBJECTIVES: To audit the implementation of national guidelines on the investigation and management of RhD disease in Tayside. SETTING: Tayside region. DESIGN: An eight month retrospective audit. RESULTS: Two hundred and eighty eight completed pregnancies in RhD negative women were observed from a total of 1879 deliveries. Of these, 120 RhD negative and 169 RhD positive babies were delivered from women who had not previously been sensitised. At delivery, anti-D was used appropriately in all cases. Of those assessed to require anti-D (n = 168), 91% received it within 24 hours of delivery. In 59 RhD negative subjects, 75 potential sensitising events occurred antenatally. In 45 of these, the event occurred after 20 weeks gestation and 44 received appropriate anti-D. In 11 (23.7%) of these, no foetomaternal haemorrhage assessment was carried out. CONCLUSION: Despite a significant increase in awareness of antenatal prophylaxis since a previous audit in the region, there is still a significant failure to request FMH assessments following potential antenatal sensitising episodes and after delivery. During the audit period, an EDTA plasma gell-based antibody detection system was commissioned in the region. This has allowed the introduction of internal laboratory referral for FMH assessment. This has allowed accurate knowledge on the possible occurrence of FMH at delivery, but has not had a significant impact on antenatal events.

CHO expression of a novel human recombinant IgG1 anti-RhD antibody isolated by phage display.

Replacement of the hyperimmune anti-Rhesus (Rh) D immunoglobulin, currently used to prevent haemolytic disease of the newborn, by fully recombinant human anti-RhD antibodies would solve the current logistic problems associated with supply and demand. The combination of phage display repertoire cloning with precise selection procedures enables isolation of specific genes that can then be inserted into mammalian expression systems allowing production of large quantities of recombinant human proteins. With the aim of selecting high-affinity anti-RhD antibodies, two human Fab libraries were constructed from a hyperimmune donor. Use of a new phage panning procedure involving bromelin-treated red blood cells enabled the isolation of two high-affinity Fab-expressing phage clones. LD-6-3 and LD-6-33, specific for RhD. These showed a novel reaction pattern by recognizing the D variants D(III), D(IVa), D(IVb), D(Va), D(VI) types I and II. D(VII), Rh33 and DFR. Full-length immunoglobulin molecules were constructed by cloning the variable regions into expression vectors containing genomic DNA encoding the immunoglobulin constant regions. We describe the first, stable, suspension growth-adapted Chinese hamster ovary (CHO) cell line producing a high affinity recombinant human IgG1 anti-RhD antibody adapted to pilot-scale production. Evaluation of the Fc region of this recombinant antibody by either chemiluminescence or antibody-dependent cell cytotoxicity (ADCC) assays demonstrated macrophage activation and lysis of red blood cells by human lymphocytes. A consistent source of recombinant human anti-RhD immunoglobulin produced by CHO cells is expected to meet the stringent safety and regulatory requirements for prophylactic application.

Responsabilidad médico-legal de los obstetras / Responsability medicolegal of obstetrician

Deberes y derechos de los obstetras. Sus responsabilidades: presupuestos, prueba, sujeto pasivo, eximentes. Situaciones particulares: embarazo, aborto, cesárea, esterilización. Apéndice legal: Ley 17132, Ley 23413, Ley 23674, Ley 24540, Código de Etica de la Confederación Médica Argentina