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Objective: Hemolytic disease of the fetus and newborn is characterized by fetal anemia, secondary to maternal alloantibody-mediated fetal erythrocyte destruction. Despite our reliance on intrauterine blood transfusion (IUT) to maintain severely affected pregnancies, it remains difficult to predict the fetal response to an infusion of donor blood. Our objective was to determine the daily rate of decline in fetal hemoglobin following one, two, and three transfusions. We also evaluated the relationship between the fetal hemoglobin level and the corresponding doppler measurement of the fetal middle cerebral artery peak systolic velocity (MCA-PSV).Study Design: A prospective observational study of all singleton pregnancies treated with intrauterine transfusion for fetal anemia secondary to maternal alloimmunization at the National Maternity Hospital, a tertiary referral centre, was conducted over a 10-year period (2011-2020). Demographic and clinical data was obtained from the electronic patient records. Ethical approval was granted by the Ethics and Research Committee of the National Maternity Hospital.Results: A total of 90 intrauterine blood transfusions were performed in 41 fetuses affected by maternal alloimmunization, of which 70% (n = 29), 34% (n = 14) and 15% (n = 6) required a 2nd, 3rd, and 4th transfusion, respectively. The mean rate of decline in fetal hemoglobin following the first transfusion was 0.4 g/dl/day (range, 0.12-0.64 g/dl/day). The mean rate of decline was lower after repeat transfusions at 0.27 g/dl/day (range, 0.16-0.45 g/dl/day). The sensitivity of MCA-PSV threshold of 1.5 Multiples of the Median (MoM) to detect moderate-severe anaemia declined with rank of IUT, from 82% after one previous transfusion, to 75% after two or more previous transfusions. No fetal mortality was seen in our series.Conclusion: Knowledge of the expected rate of decline in fetal hemoglobin following an IUT aids in the determination of appropriate timing of subsequent transfusions in a fetus affected by red cell alloimmunization. We observed a reducing rate of daily decline in hemoglobin in fetuses requiring successive transfusions. Our findings suggest a reduced accuracy of the MCA-PSV threshold of 1.5 MoM in determining the optimal timing of 2nd, 3rd, and 4th transfusions. [ABSTRACT FROM AUTHOR]

Objective: To train healthcare professionals involved in the care of Rh-D negative pregnant women, with the aim of standardizing the management of Rh isoimmunization prevention, timely antenatal diagnosis of Rh disease, fetal assessment, and treatment of fetuses with Rh disease, in order to prevent adverse perinatal outcomes., Materials and Methods: A group of 23 expert panelists participated in the development of the consensus through three rounds, answering a questionnaire consisting of 8 domains and 22 questions. A modified Delphi method was used until the consensus threshold among participants was reached, defined as 80% or greater agreement in responses. In the third round of the expert panel, a twenty-third question emerged, which was answered by one of the thematic leaders. The eight domains of antenatal management for Rh-D negative pregnant women were: 1) Rh-D determination, 2) initial prenatal care for Rh-D negative patients, 3) titration and periodicity of the indirect Coombs test, 4) sensitizing events, 5) administration of anti-D immunoglobulin (IgG), 6) Doppler velocimetry of the middle cerebral artery (MCA), 7) antenatal management of isoimmunized patients and anemic fetuses, and 8) timing for pregnancy termination based on different clinical scenarios. Based on these responses, and a review of international clinical practice guidelines, consensus statements were formulated, including recommendations, their justification, and adaptation to the local context., Results: The following recommendations were issued: It is suggested that Rh-D negative women of childbearing age attend a preconception consultation. It is recommended to determine maternal Rh-D status at the first contact with health services, either during the preconception consultation or at the first prenatal check-up. For Rh-D negative patients, it is recommended to determine the Rh-D status of the child's father during prenatal care as early as possible, preferably before the 28th week of gestation. For Rh-D negative primigravidas, where the father is Rh-D positive, it is suggested to: a) determine and quantify Rh-D antibodies (indirect Coombs test) during the first consultation and then quarterly, b) expand the obstetric history, with an emphasis on identifying sensitizing events, and c) provide parental counseling regarding potential risks, the need for additional tests, and the possibility of immunization during pregnancy. During prenatal care for Rh-D negative multiparous patients with previous Rh-D positive offspring, the initial approach should include: a) determining and titrating Rh-D antibodies (indirect Coombs test); b) expanding the obstetric history, focusing on sensitizing events; and c) providing parental counseling about potential risks and additional tests. After a sensitizing event, it is recommended to administer anti-D IgG within the first 72 hours at a dose of 1500 IU (300 μg). If not feasible, it can be administered up to 4 weeks after the event if it was not given initially. 7.1. For non-isoimmunized pregnant women (with a negative Coombs test and Rh-positive newborn), it is recommended to administer anti-D IgG between weeks 28 and 32, and within the first 72 hours postpartum if the newborn is Rh-positive. The dose is 300 μg IM or IV. 7.2. In the case of a cesarean section in an Rh-D negative patient with a Rh-D positive child, the consensus does not recommend doubling the dose of anti-D IgG. The dose remains the same as after a vaginal delivery: 300 μg IM or IV. 7.3. In a twin delivery involving an Rh-D negative patient with two or more Rh-D positive live-born infants, the consensus recommends not doubling the dose of anti-D IgG. The dose remains 300 μg IM or IV, the same as after a vaginal delivery. 7.4. For a non-isoimmunized Rh-D negative patient in the puerperium with immediate postpartum surgical tubal sterilization and an Rh-D positive neonate, anti-D IgG is recommended, assuming no prior sensitization, given the potential for reproductive decision changes or failure of the procedure. An Rh-D negative patient is considered isoimmunized if: a) the indirect Coombs test is positive at any titer, provided anti-D IgG was not received in the previous month, or b) there is a history of adverse perinatal outcomes associated with Rh disease in prior pregnancies, such as hydrops. 9.1. If Rh-D negative women are isoimmunized, it is necessary to determine the anti-D antibody titer, as this titer correlates with the severity of the disease and determines the need for fetal anemia studies with Doppler velocimetry of the MCA. 9.2. For isoimmunized Rh-D negative patients, it is recommended to follow up with monthly quantitative indirect Coombs tests until week 24, then bi-weekly, or until reaching a critical titer (≥ 1:16). 10.1. Doppler ultrasound of the MCA is suggested for Rh-D negative patients with a positive indirect Coombs test and titers ≥ 1:16. 10.2. In non-isoimmunized Rh-D negative patients, the consensus does not recommend MCA Doppler velocimetry. 10.3. Weekly MCA Doppler ultrasounds are recommended for isoimmunized patients with indirect Coombs titers ≥ 1:16. 10.4. The consensus suggests adopting a cut-off value of ≥ 1.5 multiples of the median (MoM) of the peak systolic velocity for gestational age on MCA Doppler, as this value best correlates with fetal anemia. The consensus suggests Cordocentesis when fetal anemia is suspected, and intrauterine fetal transfusion when cordocentesis shows severe fetal anemia. This procedure should be performed by trained personnel. It is recommended to prolong pregnancy until the fetus has achieved sufficient lung and tissue maturation to improve perinatal survival, according to the indirect Coombs test titer threshold., Conclusions: It is essential to address Rh-D negative pregnant women, isoimmunized women, and fetuses with Rh disease in an appropriate and standardized manner, according to the Colombian context, across all levels of prenatal care. The recommendations issued in this consensus are expected to improve clinical care, as well as enhance perinatal health and neonatal quality of life in cases of Rh disease.

The introduction of anti‐Rh(D) immunoglobulin more than 50 years ago has resulted in only a 50% decrease in Rhesus disease globally owing to a low uptake of this prophylactic approach. The International Federation of Gynecology and Obstetrics, International Confederation of Midwives, and Worldwide Initiative for Rhesus Disease Eradication have reviewed current evidence regarding the utility of anti‐Rh(D) immunoglobulin. Taking into account the effectiveness anti‐Rh(D), the new guidelines propose adjusting the dose for different indications and prioritizing its administration by indication. These FIGO/ICM guidelines review the evidence regarding the usefulness of anti‐Rh(D) immunoglobulin, prioritizing its administration by indication. [ABSTRACT FROM AUTHOR]

• Incidence of anti-D alloimmunization is estimated at 0.9 per 1000 births in France. • Anti-D immunoprophylaxis reduced the incidence of alloimmunization by 80%. • The value of anti-D prophylaxis in the first trimester has never been demonstrated. • In 2018, prevention in the first trimester of pregnancy cost €42,000 in our hospital. • Change of practice in France could reduce costs by around 60%. Anti-D alloimmunization in the first trimester of pregnancy has long been the subject of prevention with anti-D immunoglobulins during events at risk of fetomaternal hemorrhage. Although the efficacy of preventing anti-D alloimmunization by an injection of immunoglobulin at 28 weeks of gestation (WG) is obvious, the literature provides little evidence of the effectiveness before 12+6 WG and several countries have modified their recommendations. In the presumed absence of a difference in alloimmunization risk between early and late prevention, our objective was to evaluate and compare the cost of treatment for 3 alloimmunization prevention strategies in France, the United Kingdom, and the Netherlands. This was a single-center retrospective study. Our target population included all women who received anti-D immunoglobulins (Rhophylac) in the first trimester of pregnancy before 12+6 WG at Nantes University Hospital in 2018 (N = 356). Within the target population, 2 other populations were constituted based on British (N = 145) and Dutch (N = 142) clinical practice guidelines (CPG). These 3 populations were analyzed for the comparative cost of treatment for prevention from a health system perspective. The average cost of Rhophylac alloimmunization prevention for 1 episode was €117.8 from a health system perspective. The total cost attributed to prevention in 2018 at Nantes University Hospital (N = 356) was €41,931.4 according to this perspective. If the UK CPG or Dutch CPG had been applied to the Nantes target population, a saving of around 60% would have been achieved. At the national level, the cost according to the health system perspective specifically attributable to induced abortion (N estimated = 26,916) could represent a total cost of €3,170,704. This study highlighted the high cost of the French prevention strategy in the first trimester of pregnancy compared with British or Dutch strategies. The modification of our practices would allow substantial financial savings to the French health system but would also avoid the nonrecommended exposure to a blood product at this term, would allow a faster medical management and a relief of the care system. [ABSTRACT FROM AUTHOR]

Objective: To compare the effect of Delayed Cord Clamping (DCC) to Immediate Cord Clamping (ICC) on phototherapy treatment in a cohort of cesarean-delivered newborns with AB0-alloimmunization.Study Design: In a retrospective cohort study neonates with Gestational Age (GA) ≥ 35 weeks and diagnosed with AB0-alloimmunization before implementation of DCC (ICC group) were compared with neonates born after implementation (DCC group). The primary outcome was the need for phototherapy. Secondary outcomes included hospital stay, readmission rate, need for extra intravenous fluids, maximum bilirubin concentration, and hours of life at bilirubin peak. We used regression models to adjust for weight loss, type of feeding, birth weight, and gestational age.Results: In total 336 neonates were included, of which 192 neonates in the ICC group and 144 in the DCC group. There were no differences in basic characteristics between the two groups except for birth weight (ICC 3193 ± 468 g vs. DCC 3053 ± 446 g, p = 0.01) and GA (ICC 38.2 ± 1 weeks of GA, vs. DCC 37.9 ± 1 weeks of GA; p = 0.01). When adjusted for confounding factors, after implementation of DCC, significantly more infants with AB0 alloimmunization needed phototherapy (22.4% vs. 36.8%, RR 1.61 CI: 1.15–2.28; p = 0.006; Number Needed to Harm 7), needed to stay longer in hospital (20.3% vs. 30.5%, RR 1.53 CI: 1.05–2.23; p = 0.03). The maximum bilirubin was higher (11.4 ± 4.0 mg/dl vs. 12.9 ± 3.5 mg/dl, p < 0.001) and occurred later [74 (67–92) hours vs. 84 (70–103) hours; p = 0.04]. There was no difference in the need for intravenous fluids (1.6% vs. 4.9%; not significant) and readmissions (1.6% vs. 3.5%; not significant).Conclusion: Infants with AB0 alloimmunization needed more often phototherapy and were admitted longer after implementation of DCC policy. Further studies are needed to see whether the benefit of DCC outweighs the increased morbidity, admission days, and related hospital costs.

Objective: To determine whether a policy of offering cffDNA testing to all RhD-negative women at about 16 weeks' gestation to avoid anti-D administration when the fetus is RhD-negative could be implemented successfully in the NHS without additional funding.Design: Prospectively planned observational service implementation pilot and notes audit.Setting: Three maternity services in the South West of England.Population: All RhD-negative women in a 6-month period.Methods: Prospective, intervention, cross-sectional observational study, using pre-intervention data as controls.Main Outcome Measures: Proportion of suitable women who offered and accepted the test. Accuracy of the cffDNA result as assessed by cord blood group result. Fall in anti-D doses administered.Results: 529 samples were received; three were unsuitable. The results were reported as RhD-positive (n = 278), RhD-negative (n = 185) or inconclusive, treat as positive (n = 63). Cord blood results were available in 502 (95%) and the only incorrect result was one case of a false positive (cffDNA reported as positive, cord blood negative - and so given anti-D unnecessarily). The notes audit showed that women who declined this service were correctly managed and that anti-D was not given when the fetus was predicted to be RhD-negative. The total use of anti-D doses fell by about 29% which equated to about 35% of RhD-negative women not receiving anti-D in their pregnancy unnecessarily.Conclusions: We recommend this service is extended to all UK NHS services. [ABSTRACT FROM AUTHOR]

We describe two infants with severe hemolytic disease of the fetus and newborn (HDFN) with hepatosplenomegaly treated with intravenous immunoglobulin. Packed red blood cells (PRBC) were transfused resulting in an acute disproportionate increase in hemoglobin with clinical consequences in one case. These cases appear to highlight previously unreported sequelae. We discuss a hypothetical mechanism and suggest that the effect warrants further research as a possible way to decrease the need for and risks of PRBC transfusion in HDFN. [ABSTRACT FROM AUTHOR]

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Objective: To evaluate the optimal interval between middle cerebral artery (MCA) Doppler measurements when monitoring pregnancies complicated by red cell alloimmunization. Methods: Thirty-nine fetal blood samplings (FBS) performed on 24 pregnant women with red blood cell alloimmunization followed up using both MCA peak systolic velocity and time-averaged mean velocity measurements on weekly basis. Results: In total, 65.5 and 37.5% of women with moderate or severe fetal anemia had abnormal MCA Doppler values 1 and 2 weeks, respectively, before FBS was performed. Conclusions: A weekly assessment of women at risk for fetal anemia is optimal in most of the cases even though 35.5% of cases of moderate or severe fetal anemia are expected to have normal Doppler measurements the week before the decision of doing an FBS is made. [ABSTRACT FROM AUTHOR]

Objectives To compare different normal reference ranges of fetal blood flow velocity in the middle cerebral artery for predicting fetal anemia. Methods Eight reference ranges of either middle cerebral artery peak or time-averaged mean velocities were compared using the area under the receiver-operating characteristics (ROC) curve for 113 fetal blood samples from 60 women at risk of fetal red blood cell alloinimunization. Results The areas under the ROC curves of the different ranges were not significantly different but there were marked differences in sensitivity(range, 7.14–91.78%) and specificity (range, 31.25–96.88%) with the currently used cut-offs. Except for Man's range, the best theoretical cut-offs, defined as those having the best sensitivity with the best specificity, differed from those in current use, especially when using time-averaged mean velocity. Conclusions Any of the previously reported reference ranges perform well in the non-invasive prediction of fetal anemia. However, with the exception of Man's curve, the currently employed cut-offs for predicting fetal anemia should be changed, some of them markedly, in order to provide reliable support for clinical decisions. [ABSTRACT FROM AUTHOR]

Objective To compare the accuracy of Doppler velocimetry (middle cerebral artery peak systolic velocity, MCA- PSV) and amniocentesis (amniotic fluid delta optical density 450 (OD450)) for the detection of fetal anemia against the gold standard of fetal blood sampling (FBS). Methods Thirty-eight pregnancies were identified to be at risk of fetal anemia from immune causes between January 2000 and May 2002. In a cross-sectional diagnostic accuracy study, MCA-PSV and amniotic fluid delta OD450 values were plotted on reference charts and compared to an FBS obtained within the subsequent 7 days. Receiver-operating characteristics (ROC) curves were used and the area under the curve (A UC) calculated to compare the overall accuracy of the two tests. Sensitivity, specificity and likelihood ratios for positive (LR+) and negative (LR-) test results were generated for specific thresholds of MCA-PSV and delta 0D450. Results For MCA-PSV (n = 38), the AUG was 0.71 (95% Cl 0.57–0.85) and for amniotic fluid delta OD450 (n = 22) it was 0.68 (95% Cl 0.49–0.87) compared with FBS within 7 days. Sensitivity, specificity and LR+, LR- for MGA-PSV were 64%, 81%, 3.4 and 0.5, respectively, and 53%, 71%, 1.9 and 0.7 for amniotic fluid OD450, respectively. Conclusion MCA-PSV and OD450 have similar test accuracy in detecting fetal anemia. MGA-PSV is non- invasive and therefore presents no risk of miscarriage or preterm labor and thus is a preferable method of screening for fetal anemia. [ABSTRACT FROM AUTHOR]

Placental abruption is an unpredictable severe complication in pregnancy. In order to investigate the possibility that the activation of the fetal nonadaptive immune system may be involved in the pathogenesis of this disease, IL-6 release from cord blood monocytes was examined by intracellular cytokine staining and flow cytometric analysis. Our results demonstrate that preterm placental abruption (n = 15) in contrast to uncontrollable preterm labor (n = 33) is associated with significantly (P < 0.001) increased release of IL-6 from the fetal monocytes. The same holds true for rhesus disease (n = 9, P < 0.001) that is characterized by a maternal production of antibodies against the rhesus-D antigen expressed by the fetal erythrocytes. This suggests that during rhesus disease, IL-6 release of monocytes is induced by antibody-mediated cross-linking of these cells to the erythrocytes in the fetal circulation. Hence, this assumption favors the idea that also in case of placental abruption, an increased maternal antibody production against paternal antigens leads to an elevated IL-6 release by the fetal monocytes. To elucidate this potential mechanism, the presence of anti-HLA-antibodies was assessed in the maternal circulation of patients with placental abruption (n = 17) and patients with uncontrollable preterm labor (n = 29). The percentage of women producing anti-paternal HLA-antibodies was significantly (P < 0.01) increased in the group of women with preterm placental abruption (47%) in comparison to women with uncontrollable preterm labor (14%). Therefore, our results suggest that an increased humoral immune response of the mother against the fetus may be decisively involved in the pathogenesis of placental abruption. [Copyright &y& Elsevier]

Objective: To compare the effect of Delayed Cord Clamping (DCC) to Immediate Cord Clamping (ICC) on phototherapy treatment in a cohort of cesarean-delivered newborns with AB0-alloimmunization. Study Design: In a retrospective cohort study neonates with Gestational Age (GA) ≥ 35 weeks and diagnosed with AB0-alloimmunization before implementation of DCC (ICC group) were compared with neonates born after implementation (DCC group). The primary outcome was the need for phototherapy. Secondary outcomes included hospital stay, readmission rate, need for extra intravenous fluids, maximum bilirubin concentration, and hours of life at bilirubin peak. We used regression models to adjust for weight loss, type of feeding, birth weight, and gestational age. Results: In total 336 neonates were included, of which 192 neonates in the ICC group and 144 in the DCC group. There were no differences in basic characteristics between the two groups except for birth weight (ICC 3193 ± 468 g vs. DCC 3053 ± 446 g, p = 0.01) and GA (ICC 38.2 ± 1 weeks of GA, vs. DCC 37.9 ± 1 weeks of GA; p = 0.01). When adjusted for confounding factors, after implementation of DCC, significantly more infants with AB0 alloimmunization needed phototherapy (22.4% vs. 36.8%, RR 1.61 CI: 1.15-2.28; p = 0.006; Number Needed to Harm 7), needed to stay longer in hospital (20.3% vs. 30.5%, RR 1.53 CI: 1.05-2.23; p = 0.03). The maximum bilirubin was higher (11.4 ± 4.0 mg/dl vs. 12.9 ± 3.5 mg/dl, p < 0.001) and occurred later [74 (67-92) hours vs. 84 (70-103) hours; p = 0.04]. There was no difference in the need for intravenous fluids (1.6% vs. 4.9%; not significant) and readmissions (1.6% vs. 3.5%; not significant). Conclusion: Infants with AB0 alloimmunization needed more often phototherapy and were admitted longer after implementation of DCC policy. Further studies are needed to see whether the benefit of DCC outweighs the increased morbidity, admission days, and related hospital costs.

A patient presented with infertility 28 years after receiving four intrauterine transfusions as a fetus for rhesus haemolytic disease. Extensive adhesions were found in the peritoneal cavity affecting in particular the ovarian retrieval mechanism. No other possible cause for the situation could be discerned. Patients who have undergone pioneering techniques such as this are now adults and may be trying to conceive. When confronted by such a history there is therefore a need for early thorough investigation of the tubal peritoneal factor. [ABSTRACT FROM PUBLISHER]

Clinical experience with Rhesus (Rh) disease and its post-icteric sequelae is limited among high-income countries because of nearly over four decades of effective prevention care. We hypothesized that Rh disease is prevalent in other regions of the world because it is likely that protection is limited or non-existent. Following a worldwide study, it has been concluded that Rh hemolytic disease is a significant public health problem resulting in stillbirths and neonatal deaths, and is a major cause of severe hyperbilirubinemia with its sequelae, kernicterus and bilirubin-induced neurologic dysfunction. Knowing that effective Rh-disease prophylaxis depends on maternal blood-type screening, healthcare afforded to the high-risk mothers needs to be free of bottlenecks and coupled with unfettered access to effective Rh-immunoglobulin. Future studies that match the universal identification of Rh-negative status of women and targeted use of immunoprophylaxis to prevent childhood bilirubin neurotoxicity are within reach, based on vast prior experiences., (Copyright © 2014. Published by Elsevier Ltd.)