Fetal Anemia: Determinants and Perinatal Outcomes according to the Method of Intrauterine Blood Transfusion.

INTRODUCTION: Fetal anemia from hemolytic disease treated by intrauterine transfusion (IUT) can be performed by intraperitoneal, intracardiac, and intravascular transfusion (IVT). Objective of our study was to compare different transfusion techniques. METHODS: Retrospective review of IUT secondary to red cell alloimmunization was conducted at eight international centers from 2012 to 2020. Severe anemia suspected if middle cerebral artery peaks systolic velocity ≥1.5 multiples of the median. Demographic, delivery, and postnatal variables were analyzed. RESULTS: Total of 344 procedures, 325 IVT and 19 other techniques (non-IVT) included. No difference in demographics, history of stillbirth (20.5 vs. 15.8%, p = 0.7), prior pregnancy IUT (25.6 vs. 31.6%, p = 0.5) or neonatal transfusion (36.1 vs. 43.8%, p = 0.5). At first IUT, non-IVT had higher hydrops (42.1% vs. 20.4%, p = 0.03), lower starting hematocrit (13.3% [±6] vs. 17.7% [±8.2], p = 0.04), and trend toward lower gestational age (24.6 [20.1-27] vs. 26.4 [23.2-29.6] weeks, p = 0.08). No difference in birthweight, neonatal phototherapy, exchange, or simple transfusion was observed. CONCLUSION: This is one of the largest studies comparing techniques to treat fetal anemia. IVT was most performed, other techniques were more likely performed in hydrops, and lower starting hematocrit was seen. Neither technique affected outcomes. This study may suggest that physician's experience may be the strongest contributor of outcomes.

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.

Outcome predictors for maternal red blood cell alloimmunisation with anti-K and anti-D managed with intrauterine blood transfusion.

Red blood cell (RBC) alloimmunisation with anti-D and anti-K comprise the majority of cases of fetal haemolytic disease requiring intrauterine red cell transfusion (IUT). Few studies have investigated which haematological parameters can predict adverse fetal or neonatal outcomes. The aim of the present study was to identify predictors of adverse outcome, including preterm birth, intrauterine fetal demise (IUFD), neonatal death (NND) and/or neonatal transfusion. We reviewed the records of all pregnancies alloimmunised with anti-K and anti-D, requiring IUT over 27 years at a quaternary fetal centre. We reviewed data for 128 pregnancies in 116 women undergoing 425 IUTs. The median gestational age (GA) at first IUT was significantly earlier for anti-K than for anti-D (24·3 vs. 28·7 weeks, P = 0·004). Women with anti-K required more IUTs than women with anti-D (3·84 vs. 3·12 mean IUTs, P = 0·036) and the fetal haemoglobin (Hb) at first IUT was significantly lower (51.0 vs. 70.5 g/l, P = 0·001). The mean estimated daily decrease in Hb did not differ between the two groups. A greater number of IUTs and a slower daily decrease in Hb (g/l/day) between first and second IUTs were predictive of a longer period in utero. Earlier GA at first IUT and a shorter interval from the first IUT until delivery predicted IUFD/NND. Earlier GA and lower Hb at first IUT significantly predicted need for phototherapy and/or blood product use in the neonate. In the anti-K group, a greater number of IUTs was required in women with a higher titre. Furthermore, the higher the titre, the earlier the GA at which an IUT was required in both groups. The rate of fall in fetal Hb between IUTs decreased, as the number of transfusions increased. Our present study identified pregnancies at considerable risk of an unfavourable outcome with anti-D and anti-K RBC alloimmunisation. Identifying such patients can guide pregnancy management, facilitates patient counselling, and can optimise resource use. Prospective studies can also incorporate these characteristics, in addition to laboratory markers, to further identify and improve the outcomes of these pregnancies.

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.

Delayed cord clamping in Rh-alloimmunised infants: a randomised controlled trial.

Despite advancement in medical care, Rh alloimmunisation remains a major cause of neonatal hyperbilirubinaemia, neuro-morbidity, and late-onset anaemia. Delayed cord clamping (DCC), a standard care now-a-days, is yet not performed in Rh-alloimmunised infants due to paucity of evidence. Hence, we randomised these infants of 28- to 41-week gestation to delayed cord clamping (N = 36) or early cord clamping (N = 34) groups. The primary outcome variable was venous packed cell volume (PCV) at 2 h of birth. The secondary outcomes were incidence of double volume exchange transfusion (DVET) and partial exchange transfusion (PET), duration of phototherapy (PT), functional echocardiography (parameters measured: superior vena cava flow, M-mode fractional shortening, left ventricular output, myocardial perfusion index, and inferior vena cava collapsibility) during hospital stay, and blood transfusion (BT) until 14 weeks of life. Neonates were managed as per unit protocol. The baseline characteristics of enrolled infants were comparable between the groups. The median (IQR) gestation and mean (SD) birth weight of enrolled infants were 35 (33-37) weeks and 2440 (542) g, respectively. The DCC group had a higher mean PCV at 2 h of life (48.4 ± 9.2 vs. 43.5 ± 8.7, mean difference 4.9% (95% CI 0.6-9.1), p = 0.03). However, incidence of DVET and PET, duration of PT, echocardiography parameters, and BT until 14 weeks of postnatal age were similar between the groups.Conclusion: DCC in Rh-alloimmunised infants improved PCV at 2 h of age without significant adverse effects.Trial registration: Clinical Trial Registry of India (CTRI), Ref/2016/11/012572 http://ctri.nic.in/Clinicaltrials, date of trial registration 19.12.2016, date of first patient enrolment 1 January 2017.What is Known:•Delayed cord clamping improves haematocrit, results in better haemodynamic stability, and decreases the need of transfusion in early infancy.•However, due to lack of evidence, potential risk of hyperbilirubinaemia, and exacerbation of anaemia (following delayed cord clamping), early cord clamping is the usual norm in Rh-alloimmunised infantsinfants.What is New:•Delayed cord clamping in Rh-alloimmunised infants improves haematocrit at 2 h of life without any increase in incidence of serious adverse effects.

Evaluation of Rh-Hemolytic Disease in Neonates and Management with Early Intensive Phototherapy in the Neonatal Intensive Care Unit.

BACKGROUND OF THE STUDY: In neonates with Rh-hemolytic disease, light emitting diode (LED) phototherapy allows delivery of high spectral irradiance (SI). A linear correlation exists between SI and efficacy of phototherapy with no saturation point. There is scant data on evaluation and early phototherapy using LED units in Rh-hemolytic disease. OBJECTIVE: This study aimed to describe the hemoglobin (Hb), hematocrit (Hct), total serum bilirubin (TSB), phototherapy parameters and short-term outcomes in neonates with Rh-hemolytic disease. METHODOLOGY: Maternal parameters for Rh-isoimmunization were recorded and monitoring of fetal anemia by Doppler ultrasound was done. Early intensive phototherapy within 1 h of birth was initiated for cord blood Hb below 13.6 g/dl and/or TSB greater than 2.8 mg/dl. RESULTS: Fifty Rh positive neonates were enrolled of which 11/50 (22%) received intrauterine transfusions. The maximum TSB remained below 18 mg/dl in 42/50 (84%) of neonates. The mean SI on the trunk was 56.260 ± 8.768 µW/cm2/nm and duration of phototherapy was 7 ± 3.29 days (mean ± SD). There was a positive correlation between strength of indirect antiglobulin test and cord blood Hb: correlation coefficient (r) = 0.295; direct antiglobulin test and duration of phototherapy: r = 0.331. Early packed red blood cell (PRBC) transfusion was required in 8/50 (16%) neonates while 20/50 (40%) required late transfusions. CONCLUSION: With a mean SI of 56.260 ± 8.768 µW/cm2/nm on the trunk, TSB remained below 18 mg/dl in majority thereby avoiding exchange transfusion. Early or late PRBC transfusion requirement was 1 (1-2) (median ± interquartile range).

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.

How clinically important are non-D Rh antibodies?

INTRODUCTION: The advent of RhD immunoglobulin prophylaxis to prevent maternal RhD alloimmunization has reduced the incidence of this condition and its associated poor outcomes. Consequently, non-D Rh antibodies now account for a greater proportion of alloimmunized pregnancies. These antibodies have been the subject of comparatively little research. This study investigated the incidence and clinical outcome of pregnancies affected by non-D Rh alloimmunization at an Australian tertiary maternity service. MATERIAL AND METHODS: This was a retrospective study of all pregnancies with non-D Rh antibodies (namely anti-C, -E, -c, -e, -Cw as well as the compound antibodies anti-CD, -cE and -ce) managed at the Royal Women's Hospital, Victoria, Australia, from 2009 to 2013 inclusive. Information collected included maternal demographics, details of the antibodies, course of the pregnancy and neonatal outcomes. RESULTS: During the study period, 115 non-D Rh alloimmunized pregnancies were identified in 102 mothers. Forty-nine pregnancies reached the critical titer (> 16) from non-D Rh alone and 11 fetuses received intrauterine red blood cell transfusion. Labor was induced or cesarean section performed in 38 cases. Forty-three neonates were admitted to the special care nursery and 59 received phototherapy. Nine received treatment for anemia and 10 neonates received intravenous immunoglobulin. CONCLUSIONS: Non-D Rh alloimmunization is a relatively uncommon complication of pregnancy, occurring in only .33% of pregnancies in the study period. It can lead to significant fetal/neonatal morbidity (and may lead to mortality). The most severe outcomes (including perinatal deaths) were mostly associated with the compound antibodies anti-CD and anti-cE, or a non-D Rh antibody in conjunction with anti-D.

Hyperferritinaemia following intrauterine transfusions for Rh isoimmunisation.

Intrauterine transfusion is one of the mainstays of treatment in isoimmunised pregnancies guided by the changes in middle cerebral artery Doppler of the fetus. The common postnatal complications associated with Rh isoimmunisation are high unconjugated bilirubin requiring blood exchange transfusions, cholestasis due to bile inspissation, thrombocytopenia and anaemia. Hyperferritinaemia is an uncommon adverse effect observed in Rh isoimmunised pregnancies. In this case report, we describe the clinical course of a Rh isoimmunised neonate with hyperferritinaemia and transfusion acquired cytomegalovirus disease which resolved. Iron chelation therapy was not necessary.

Neonatal hyperbilirubinemia secondary to combined anti e and anti C isoimmunisation: a literature review.

A term male infant was admitted at 48 h of postnatal life to the neonatal unit for jaundice. The investigation showed total serum bilirubin (TSB) of 17.1 mg/dl, haemoglobin of 11 g/dl, reticulocyte count of 9.5% and peripheral smear was suggestive of macrocytic, normochromic red blood cell (RBC) with target cells and multiple spherocytes with occasional nucleated RBC. The infant's blood group was B positive. Direct antiglobulin test was strongly positive by gel method (3+). Mother's blood group was B positive and indirect antiglobulin test was positive when tested postnatally. Extended minor blood grouping and cross matching showed this as a case of combined anti e and anti C antibodies isoimmunisation. Infant was treated with phototherapy for 72 h and was shifted to mother side. Infant was serially monitored with TSB level every sixth hourly and American Academy of Pediatrics (AAP) phototherapy charts were followed to see for rebound hyperbilirubinemia. The neonate was discharged and there was no readmission for hyperbilirubinemia. It is very rare and we report the third case of its type till date.

Chelation therapy for secondary neonatal iron over load: Lessons learned from rhesus hemolytic disease.

Khdair-Ahmad F, Aladily T, Khdair-Ahmad O, Badran EF. Chelation therapy for secondary neonatal iron overload: Lessons learned from rhesus hemolytic disease. Turk J Pediatr 2018; 60: 335-339. Secondary neonatal iron overload occurs with intrauterine and post-natal blood transfusions. Treatment with intravenous Deferoxamine was reported only in four cases in the literature. Herein we report a case of a patient born at 36 weeks of gestation, who had rhesus hemolytic disease. He developed secondary iron overload, causing liver injury, after a total of six blood transfusions: four intrauterine and 2 post-natal transfusion therapies. Intravenous Deferoxamine treatment was started at the age of 45 days due to a ferritin level of 40,000 mg/L, progressive rise of liver enzymes, and worsening cholestasis. Treatment resulted in marked reduction in ferritin level (down to 829 mg/L at the age of 6 months), significant improvement in the liver enzymes, and resolution of cholestasis.

Anti-D quantification in relation to anti-D titre, middle cerebral artery Doppler measurement and clinical outcome in RhD-immunized pregnancies.

BACKGROUND: The optimal strategy to monitor RhD-immunized pregnancies is not evident. Whether a quantitative analysis of anti-D antibodies adds valuable information to anti-D titre is unclear. The aim of this study was to evaluate the relevance of anti-D quantification in routine monitoring of RhD-immunized pregnancies. MATERIALS AND METHODS: In a retrospective study, 64 consecutive pregnancies in 61 immunized women with anti-D titre ≥128 at any time during pregnancy were included. According to routine, at titre ≥128, anti-D quantification was performed by flow cytometry and the peak systolic velocity in the middle cerebral artery was measured by ultrasound. Decisions for treatment with intrauterine blood transfusion were based on increased peak systolic velocity in the middle cerebral artery. RESULTS: Increasing anti-D concentrations correlated well to increasing anti-D titres, but at each titre value, there was a large interindividual variation, in the determined anti-D concentration. Intrauterine transfusions were initiated in 35 pregnancies according to algorithms based on ultrasound measurements, at anti-D concentrations of 2·4-619 IU/ml and titre 128-16 000. Sixty pregnancies resulted in a live-born child, three in miscarriage and one in termination of pregnancy. During the perinatal care in the neonatal intensive care unit, thirty-one of the neonates were treated with blood exchange transfusions and/or red cell transfusions and 47 were treated with phototherapy. CONCLUSION: Anti-D quantification does not add further information compared to anti-D titre, in defining a critical level to start monitoring RhD-immunized pregnancies with Doppler ultrasound.

Maternal red blood cell alloimmunization requiring intrauterine transfusion: a comparative study on management and outcome depending on the type of antibody.

BACKGROUND: The antibody primarily responsible for fetal anemia may influence treatment and prognosis. The primary objective was to compare ante- and postnatal management and the outcomes of maternal red blood cell (RBC) alloimmunizations according to the antibody involved. The secondary objective was to compare anti-D alloimmunizations according to associated number of antibodies. STUDY DESIGN AND METHODS: A single-center study from 1999 to 2015 including maternal RBC alloimmunizations requiring intrauterine transfusion (IUT) was conducted. Patients were classified according to the antibody involved: anti-D, other Rh (anti-c and anti-E), and anti-K1. Obstetric data, IUT characteristics, and neonatal outcome were compared. A specific study on the anti-D, when isolated or associated, was then conducted. RESULTS: There were 106 pregnancies included, with 77.4% having anti-D, 9.4% having another anti-Rh (Rh group), and 13.2% having anti-K1. No significant difference between the anti-D and Rh groups was found for management and prognosis. The hemoglobin level in the first IUT was higher in the anti-D group than in the Kell group (6.8 vs. 4.7 g/dL, p = 0.008). Newborns in the anti-D group had significantly higher bilirubin levels and phototherapy duration than those in the Kell group. The mean estimated daily decrease in hemoglobin and that between the first two IUTs were lower with an isolated anti-D, compared with anti-D associated with two antibodies (p = 0.04). CONCLUSION: Anti-K1 alloimmunizations seem to cause more severe fetal anemia than anti-D alloimmunizations. Moreover, a decrease in hemoglobin appears to be more rapid when anti-D is associated with other antibodies.

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.

Anti-D in a mother, hemizygous for the variant RHD*DNB gene, associated with hemolytic disease of the fetus and newborn.

BACKGROUND: Individuals with the partial D phenotype when exposed to D+ red blood cells (RBCs) carrying the epitopes they lack may develop anti-D specific for the missing epitopes. DNB is the most common partial D in Caucasians and the clinical significance for anti-D in these individuals is unknown. STUDY DESIGN AND METHODS: This article describes the serologic genotyping results and clinical manifestations in two group D+ babies of a mother presenting as group O, D+ with alloanti-D. RESULTS: The mother was hemizygous for RHD*DNB gene and sequencing confirmed a single-nucleotide change at c.1063G>A. One baby (group A, D+) displayed bilirubinemia at birth with a normal hemoglobin level. Anti-A and anti-D were eluted from the RBCs. For the next ongoing pregnancy, the anti-D titer increased from 32 to 256. On delivery the baby typed group O and anti-D was eluted from the RBCs. This baby at birth exhibited anemia, reticulocytosis, and hyperbilirubinemia requiring intensive phototherapy treatment from Day 0 to Day 9 after birth and was discharged on Day 13. Intravenous immunoglobulin was also administered. Both babies were heterozygous for RHD and RHD*DNB. CONCLUSION: The anti-D produced by this woman with partial D DNB resulted in a case of hemolytic disease of the fetus and newborn (HDFN) requiring intensive treatment in the perinatal period. Anti-D formed by women with the partial D DNB phenotype has the potential to cause HDFN where the fetus is D+. Women carrying RHD*DNB should be offered appropriate prophylactic anti-D and be transfused with D- RBCs if not already alloimmunized.

Personalized treatment with immunoadsorption and intravenous immunoglobulin in a case of severe Rh alloimmunization during pregnancy unresponsive to plasma - exchange.

INTRODUCTION: Despite prophylaxis, a small proportion of RhD-negative women may develop anti-D antibodies after a sensitizing event occurring during pregnancy or delivery of a D-positive baby. Intrauterine transfusion (IUT) is the treatment of choice in case of fetal anemia, but it cannot be performed early during pregnancy. Combined treatment with therapeutic plasma-exchange (TPE) and intravenous immunoglobulin (IVIG) can avoid or delay IUT. Immunoadsorption (IA) could represent a more effective treatment in selected cases. CASE REPORT: We report a D-negative female with a history of induced abortion and hydrops fetalis, referred at 8 weeks of gestation with a high anti-D titer. Despite implementing a TPE-IVIG protocol, the patient experienced a spontaneous abortion. At the beginning of her fourth pregnancy, only after a partially effective intensive TPE course, cycles of IA-IVIG were performed. Despite a suboptimal response on the anti-D titer, Doppler ultrasonographic measurements of the fetal middle cerebral artery peak systolic velocity first showed evidence of anemia at 30 weeks of gestation and a IUT was required. After the IUT, anemia persisted with a subsequent dramatic rise in titer, requiring an emergent cesarean section. The infant subsequently underwent successful treatment with IVIG, phototherapy and exchange transfusion and was discharged 7 weeks later without neurological deficits. DISCUSSION: The treatment of high titer anti-D antibodies during pregnancy may require a multidisciplinary approach with utilization of different apheresis strategies in order to have a successful pregnancy outcome.

Third trimester screening for alloimmunisation in Rhc-negative pregnant women: evaluation of the Dutch national screening programme.

OBJECTIVE: To evaluate the effect of red blood cell (RBC) antibody screening in the 27th week of pregnancy in Rhc-negative women, on detection of alloimmunisation, undetected at first trimester screening ('late' alloimmunisation), and subsequent haemolytic disease of the fetus and newborn (HDFN), to assess risk factors for late alloimmunisation. DESIGN: Prospective cohort and nested case-control study. SETTING: The Netherlands. POPULATION: Two-year nationwide cohort. METHODS: Prospective inclusion of Rhc-negative women with negative first trimester screening and of screen-negative controls. Assessment of incidence and numbers needed to screen (NNS) of late alloimmunisation and HDFN; logistic regression analysis to establish risk factors for late alloimmunisation. MAIN OUTCOME MEASURES: Late alloimmunisation, HDFN. RESULTS: Late alloimmunisation occurred in 99 of 62 096 (0.159%) Rhc-negative women; 90% had c/E antibodies and 10% non-Rhesus antibodies. Severe HDFN (fetal/neonatal transfusion) occurred in two of 62 096 (0.003%) of Rhc-negative women and 2% of late alloimmunisations; moderate HDFN (phototherapy) occurred in 20 children [22.5%; 95% confidence interval (CI), 13.8-31.1%]. Perinatal survival was 100%. The NNS to detect one HDFN case was 2823 (31 048 for severe, 3105 for moderate HDFN). Significant risk factors were former blood transfusion [odds ratio (OR), 10.4; 95% CI, 1.14-94.9], parity (P-1: OR, 11.8; 95% CI, 3.00-46.5; P > 1: OR, 7.77; 95% CI, 1.70-35.4) and amniocentesis/chorionic villus sampling during current pregnancy (OR, 9.20; 95% CI, 1.16-72.9). CONCLUSIONS: Additional screening of Rhc-negative women improved the detection of late alloimmunisation and HDFN, facilitating timely treatment, with a NNS of 2823. Independent risk factors for late alloimmunisation were blood transfusion, parity and chorionic villus sampling/amniocentesis in the current pregnancy. The occurrence of most factors before the current pregnancy suggests a secondary immune response explaining most late alloimmunisations. TWEETABLE ABSTRACT: Third trimester screening for alloimmunisation in Rhc-neg women improves detection and treatment of severe HDFN.

[THE FETAL MIDDLE CEREBRAL ARTERY PEAK SYSTOLIC VELOCITY AS A PEDICTOR OF FETAL ANEMIA IN RH-ALLOIMMUNIZED PREGNANCY].

UNLABELLED: Rh-isoimmunization is a pathological condition in which the fetal red blood cells of a Rh (+) fetus are destroyed by the isoantibodies of a Rh (-) woman sensitized in a previous event. Despite of the wide spread implementation of anti D-gammaglobolin prophylaxis this is still the most common cause for fetal anemia. Recently, sonographic measurement of the fetal middle cerebral artery peak systolic velocity (MCA-PSV) has been shown to be an accurate non-invasive test to predict low fetal hemoglobin levels. We present a case report of Rh-alloimmunized pregnancy with moderate fetal anemia, followed-up by weekly MCA-PSV measurements. CASE REPORT: A 37-year-old Rh (-) negative gravida 3, para 1, without anti-D gammaglobolin prophylaxis in her previous pregnancies, presented at 27+0 weeks of gestation (w.g.) for a routine third trimester scan. Subsequent ultrasound measurements of MCA-PSV confirmed a progressive increase of the peak systolic velocities from 40 to 80 cm/sec, as well as a gradual rise in the anti-D titers. The evidence of developing fetal anemia necessitated elective Caesarean section performed at 35 wg. The neonate was admitted in the intensive care unit and required resuscitation, one exchange blood transfusion and several courses of phototherapy. The patient was discharged two weeks post partum. CONCLUSIONS: There is a strong correlation between the high peak systolic velocities in the middle cerebral artery (MCA-PSV) and the low levels of fetal hemoglobin. The high sensitivity and positive predictive value concerning the development of fetal anemia, as well as its good repeatability, makes this non-invasive test a valuable asset in the management of all pregnancies complicated by severe Rh-alloimmunization.