Severe Cholestasis in Neonates with Hemolytic Disease of the Fetus and Newborn-A Case Report.

Hemolytic disease of the fetus and newborn (HDFN) may cause severe cholestasis with direct bilirubin concentrations reaching up to 50 times the upper limit of normal. This case report describes twins whose highest direct bilirubin concentrations were 32.2 mg/dL and 50.2 mg/dL, with no significant signs of hepatic impairment. The index pregnancy was complicated by Rhesus factor immunization with anti-D antibodies present in maternal serum, which caused fetal anemia requiring intrauterine blood transfusions. Complementary tests demonstrated Rhesus D alloimmunization as the sole cause of cholestasis. To the best of our knowledge, this is the first study to describe such elevated direct bilirubin concentrations caused by HDFN.

Automated quantitative evaluation of fetal atrioventricular annular plane systolic excursion before and after intrauterine blood transfusion in pregnancies affected by red blood cell alloimmunization.

INTRODUCTION: Maternal red blood cell alloimmunization during pregnancy can lead to hemolysis and various degrees of fetal anemia, which can be treated with intrauterine blood transfusion (IUT) to prevent adverse outcomes. Knowledge about fetal myocardial function and adaptation is limited. The aim of the present study was to measure fetal atrioventricular plane displacement before and after IUT and compare these measurements with previously established reference ranges. MATERIAL AND METHODS: An observational study was conducted on pregnant women affected by red blood cell alloimmunization. Fetal echocardiography was performed before and after IUT. The atrioventricular plane displacement of the left and right ventricular walls and interventricular septum, described as mitral, septal, and tricuspid annular plane systolic excursion (MAPSE, SAPSE, and TAPSE, respectively), was assessed using color tissue Doppler imaging with automated analysis software. A Mann-Whitney U test was used to compare the z scores to the normal mean before and after IUT. RESULTS: Twenty-seven fetuses were included. The mean z score for pre-IUT MAPSE was significantly increased compared with the reference ranges, +0.46 (95% confidence interval [CI] +0.17 to +0.75; p = 0.039), while the mean z scores for post-IUT SAPSE and TAPSE were significantly decreased, -0.65 (95% CI -1.11 to -0.19; p < 0.001) and -0.60 (95% CI -1.04 to -0.17; p = 0.003), respectively. The difference in atrioventricular plane displacement z scores before and after IUT was statistically significant in all three locations. The median difference between the pre-IUT and post-IUT z scores was -0.66 (95% CI -1.03 to -0.33, p < 0.001) for MAPSE, -1.05 (95% CI -1.43 to -0.61, p < 0.001) for SAPSE, and -0.60 (95% CI -1.19 to -0.01, p = 0.046) for TAPSE. CONCLUSIONS: This study suggests that atrioventricular plane displacement, when determined using automated analysis software, may represent a quantitative parameter, describing fetal myocardial function and adaptation before and after IUT.

Liver Dysfunction with Severe Cholestasis and Coagulation Disorders in the Course of Hemolytic Disease of the Newborn Requiring Chelation Therapy-A Case Report and Review of the Literature.

Severe hemolytic disease of the fetus and newborn (HDFN) requiring intrauterine transfusions (IUTs) may cause iron accumulation, resulting in liver damage, which may lead to cholestasis and coagulation disorders. In this article, we reported a case of a female neonate who underwent chelation therapy with a positive outcome, and we reviewed the English and Polish literature on chelation therapy in HDFN available in PubMed. The patient with maximum ferritin concentration above 33,511.2 ng/mL developed liver dysfunction with coagulation disorders requiring multiple transfusions of fresh frozen plasma (FFP), Octaplex® and cryoprecipitate, and hypoalbuminemia treated with numerous albumin infusions. Furthermore, severe cholestasis was observed with direct bilirubin levels up to 33.14 mg/dL. Additionally, the child developed transient myelosuppression with neutropenia, thrombocytopenia, and low reticulocyte count due to several blood transfusions. The differential diagnosis tests were conducted to rule out any causes of hepatic failure other than hemolytic disease of the newborn. This case proves that adequate treatment of severe HDFN with anemia requiring IUT and hepatic failure can lead to positive outcomes with no long-term consequences.

[Clinical Efficacy and Nursing Care of Fetal Intrauterine Blood Transfusion: Previous Experience Review].

Objective: To summarize the clinical efficacy and nursing experience of intrauterine blood transfusion (IUT) treatment for fetal anemia cases. Methods: The clinical data of 4 fetal anemia cases receiving IUT in Beijing Obstetrics and Gynecology Hospital, Capital Medical University between 2020 and 2022 were collected. Four pregnant women aged 24-38 years were included in the study. They carried fetuses with anemia of unknown causes. The four pregnant women developed anxiety after they were informed of the diagnosis of fetal anemia. One-on-one psychological counseling before the IUT procedure and one-on-one companionship over the course of the surgery were provided for the pregnant women. In addition, they were closely monitored for blood transfusion reactions. Postprocedural observation of the puncture site and 24-hour monitoring of the newborns were also conducted. Results: The four pregnant women underwent 1-3 times of IUT in the second and third trimesters, with the minimum gestational age at the time of IUT being 25 + weeks and the blood transfusion volume being 20-107 mL/time. Two pregnant women experienced irregular uterine contractions during IUT in the third trimester. Other than that, all other IUT treatments were successful. After IUT, there was a significant improvement in fetal hemoglobin, peak systolic velocity of the middle cerebral artery (MCA-PSV), and cardiothoracic area ratio. One case did not give birth in our hospital and the outcome of the fetus was not known. The other three fetuses achieved good outcomes. Conclusion: Positive preprocedural psychological counseling for pregnant women, close intraoprocedural and postprocedural pregnancy monitoring, and the prevention of maternal and fetal complications are the key to improving the clinical efficacy of IUT and achieving a good fetal outcome.

Case report: Double filtration plasmapheresis (DFPP) for severe rhesus-D alloimmunization in two pregnant patients.

Maternal erythrocyte alloimmunization is one of the most important causes of fetal anemia. The standard treatment for anemic fetuses is intrauterine blood transfusion (IUT). However, IUT may have adverse effects, particularly before 20 weeks of gestation. In this report, two women who had previously had severely affected alloimmunized pregnancy developed high titers of anti-D antibodies before 20 weeks of gestation. Ultrasound Doppler showed severe fetal anemia, and intrauterine transfusion was expected to be unavoidable. To prolong pregnancy to a gestation in which intravascular IUT was possible, we used repeated double filtration plasmapheresis (DFPP) as a rescue therapy. The titers of IgG-D, IgG-A, and IgG-B decreased after DFPP treatment. One woman successfully prolonged pregnancy until 20 weeks of gestation. Subsequently, she underwent four cycles of IUTs and delivered at 30 weeks of gestation by emergency cesarean section due to fetal bradycardia during the fifth intrauterine transfusion. The other woman successfully delayed intrauterine transfusion until 26 weeks of gestation. The favorable results of the two patients indicate that DFPP may be an effective and safe treatment modality for RhD immunity in pregnant women. Moreover, DFPP is potentially helpful for reducing the occurrence of ABO hemolytic disease in neonates due to the clearance of IgG-A and IgG-B antibodies (e.g., O pregnant women harbored A/B/AB neonates). However, more clinical trials are needed to verify the results.

Fetal anemia in monochorionic twins: a review on diagnosis, management, and outcome.

INTRODUCTION: Monochorionic twins may develop fetal anemia when blood is unequally distributed via the placental vascular anastomoses. This review focuses on the causes of fetal anemia in complicated monochorionic twins and highlights the differences in management and outcome. AREAS COVERED: Fetal anemia can occur in the context of twin anemia polycythemia sequence (TAPS), chronic twin-twin transfusion syndrome (TTTS) and acute peripartum TTTS, and in cotwins after single fetal demise. Diagnosis of fetal anemia is based on abnormal Doppler ultrasound measurements. Management options include fetoscopic laser surgery, intrauterine blood transfusion, or expectant management, depending on the type of complication and the severity of the disease. In all complications, fetal anemia may lead to perinatal mortality, neonatal morbidity, severe cerebral injury, and long-term neurodevelopmental impairment. In TAPS specifically, anemic donors may also show bilateral deafness. EXPERT OPINION: Knowledge on the diagnosis and optimal treatment in TTTS is nowadays widespread, but caregivers often fail to distinguish TAPS from acute peripartum TTTS at birth. A full blood count including reticulocyte count is required, and placental dye injection is extremely helpful to reach the correct diagnosis and establish the optimal management.

Intravenous immunoglobulin in the management of severe early onset red blood cell alloimmunisation.

Our objective was to assess the effect of maternal intravenous immunoglobulin (IVIG) administration for severe red blood cell (RBC) alloimmunisation on fetal outcomes. This is a case-control study. Women with a history of severe early onset alloimmunisation resulting in fetal loss in a previous pregnancy and high anti-D or anti-K antibody titres received IVIG in a subsequent pregnancy. We assessed gestational age at first transfusion and fetal outcomes in the subsequent pregnancy and compared these with the outcomes in the previous pregnancy. The most responsible antibody was anti-D in 17 women and anti-K in two others, whilst seven had more than one antibody. In all, 19 women received IVIG in 22 pregnancies, two of which did not even need an intrauterine transfusion (IUT). For previous early losses despite transfusion, IVIG was associated with a relative increase in fetal haemoglobin between treated and untreated pregnancies of 36.5 g/L (95% confidence interval 19.8-53.2, p = 0.0013) and improved perinatal survival (eight of eight vs. none of six, p = 0.001). For previous losses at <20 weeks, it enabled first transfusion deferral in subsequent pregnancies to at least 19.9 weeks (mean 23.2 weeks). Overall, IVIG decreases the severity of haemolytic disease of the fetus and newborn and allows deferral of the first IUT to a safer gestation in severe early-onset RBC alloimmunisation and rarely may even avoid the need for IUT entirely.

Identification and management of fetal anemia due to hemolytic disease.

INTRODUCTION: Hemolytic disease of the fetus and newborn (HDFN) is a condition caused by maternal alloantibodies against fetal red blood cells (RBCs) that can cause severe morbidity and mortality in the fetus and newborn. Adequate screening programs allow for timely prevention and intervention resulting in significant reduction of the disease over the last decades. Nevertheless, HDFN still occurs and with current treatment having reached an optimum, focus shifts toward noninvasive therapy options. AREAS COVERED: This review focusses on the timely identification of high risk cases and antenatal management. Furthermore, we elaborate on future perspectives including improvement of screening, identification of high risk cases and promising treatment options. EXPERT OPINION: In high-income countries mortality and morbidity rates due to HDFN have drastically been reduced over the last decades, yet worldwide anti-D mediated HDFN still accounts for 160,000 perinatal deaths and 100,000 patients with disabilities every year. Much of these deaths and disabilities could have been avoided with proper identification and prophylaxis. By implementing sustainable prevention, screening, and disease treatment measures in all countries this will systemically reduce unnecessary perinatal deaths. There is a common responsibility to engage in this cause.

A Rare Dichorionic Triamniotic Triplet Pregnancy with Spontaneous Twin Anemia-Polycythemia Sequence between Two Dichorionic Fetuses.

INTRODUCTION: This report presents a rare case of spontaneous twin anemia-polycythemia sequence (TAPS) between two dichorionic fetuses in a spontaneous, homozygotic, dichorionic, triamniotic, triplet pregnancy treated with multiple intrauterine blood transfusions (IUTs) and partial exchange transfusions (PETs). CASE PRESENTATION: The pregnancy was diagnosed with stage IV TAPS at gestational week 25+1. The patient was treated with laser surgery combined with multiple IUTs and PETs. The triplets were delivered at a planned caesarean section at gestational week 28+1 with postnatal hemoglobin values of 18.21, 26.43, and 11.92 g/dL in triplet 1, 2, and 3, respectively. At 4 years of age, triplet 1 is considered healthy, triplet 2 is diagnosed with mild mental retardation, and triplet 3 with profound mental retardation and dystonic cerebral palsy. DISCUSSION: This is an extremely rare case of TAPS between dichorionic fetuses in a triplet pregnancy, and routine surveillance with measurement of middle cerebral artery peak systolic velocity in dichorionic pregnancies may contribute to the detection of similar cases in the future. Furthermore, this case contributes with rare long-term follow-up data of children treated for high-stage TAPS with multiple IUTs and PETs.

Development of a Training Model for Teaching Intrauterine Fetal Blood Transfusion.

This article describes an inexpensive simulator developed for teaching intrauterine blood transfusion. The model is constructed from a boneless chicken thigh folded over a Penrose drain placed in a water-filled snap-lock lid container and covered by melted ballistic gel to simulate the fetal intrahepatic vessel. Participants valued this educational tool and reported feeling the model was practical and realistic. This low-cost, high-fidelity model provides realistic tissue resistance and represents a sonographically accurate intrahepatic fetal blood transfusion training tool.

The rate of decline in fetal hemoglobin following intrauterine blood transfusion in the management of red cell alloimmunization.

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.

Nationwide survey of intrauterine blood transfusion for fetal anemia in Japan.

AIM: The present study investigated the current situation regarding intrauterine blood transfusion (IUT) for fetal anemia in Japan. METHODS: We conducted a nationwide, multicenter, retrospective cohort questionnaire survey for cases that underwent IUT from 2011 to 2015. The questionnaire required perioperative information, indications, details of the procedure, procedure-related complications, and neonatal morbidity. RESULTS: A total of 100 IUT procedures were performed in 66 cases at 19 institutions during the study period. The most frequent indication of IUT was complicated monochorionic diamniotic (MCDA) twins in 28 (42.4%) cases, followed by 16 (24.2%) cases of red-cell alloimmunization, and 10 (15.2%) cases of parvovirus B19 infection. IUT was performed through the umbilical cord in the vast of majority cases (92%). Bleeding from the IUT site was the most common adverse event (40%). Two cases (2%) underwent emergency cesarean section after the procedure. There were no cases of rupture of membrane or intrauterine infection after IUT. The neonatal survival rate was 77.3% in the 66 total cases and 64% in the hydrops cases. The neonatal survival rates in MCDA twins, red-cell alloimmunization, and parvovirus B19 infection were 75%, 93.8%, and 70%, respectively. CONCLUSIONS: IUT was performed for mainly three indications in Japan: MCDA twins, red-cell alloimmunization, and parvovirus B19 infection. The incidences of severe adverse events seemed very low. The outcomes after IUT were favorable with variations in survival rates according to indications. However, further studies with long-term follow-up will be required to assess the effectiveness of IUT, especially for complicated MCDA twins.

Peak systolic velocity of fetal middle cerebral artery to predict anemia in Red Cell Alloimmunization in un-transfused and transfused fetuses.

OBJECTIVE: To assess the accuracy of middle cerebral artery peak systolic velocity (MCA-PSV) in prediction of severe fetal anemia resulting from Red Cell Alloimmunization (Anti-D) in un-transfused and transfused fetuses. In addition to comparing the accuracy of MCA-PSV and the estimation of the daily decline of fetal hemoglobin (Hb), to determine the appropriate time of subsequent transfusions. STUDY DESIGN: This was a retrospective study of a series of 84 anaemic fetuses due to Red Cell alloimmunization. During each in-utero transfusion session, measurements of (1)MCA-PSV, (2)pre- and (3)post-transfusion Hb levels were recorded. Receiveroperating characteristics (ROC) curves, negative and positive predictive values of MCA-PSV in predicting severe fetal anemia were calculated. Regression analysis assesses the correlation between fetal HB and MCA-PSV, and between observed and expected fetal hemoglobin levels. RESULTS: Eighty four anemic fetuses were included in the study and had an in-utero transfusion. The positive predictive value (PPV) of MCAPSV decreased sharply from 86.0 % at the first IUT, to 52.0 % and 52.1 % at the second and third IUTs respectively. According to the ROC curves, setting the cut-off at 1.70 MoM would provide the best performance of MCA-PSV with respect to the timing of the second and third IUT. Setting a higher threshold of 1.70 MoM for the 2nd and 3rd transfusions would increase the PPV from 52.0 % to 96.4 % at the second IUT, and from 52.1%-99.8 % at the third IUT. CONCLUSION: In this study we suggest that a higher MCA-PSV (MoM 1.7 in compared to 1.5MOM) can accurately predict the recurrence of severe fetal anemia requiring serial IUTs. In transfused fetuses, MCAPSV accuracy to detect severe anemia decline slightly with increase number of IUT. In addition to that, the mean projected daily decrease in fetal hemoglobin has a similar accuracy to MCA-PSV in predicting moderate to severe fetal anemia.

Preparation and clinical application of 0.7~0.8 hematocrit concentrated washed red blood cells in intrauterine blood transfusion for fetal anemia / 中国输血杂志

【Objective】 To develop a new approach for the preparation of 0.7~0.8 hematocrit concentrated washed red blood cells(RBCs) for fetal anemia in utero transfusion and apply it in clinical. 【Methods】 The erythrocyte suspension and frozen stored erythrocytes within expiry date in Guangzhou Blood Center from March 2020 to February 2021 were taken to prepare concentrated washed RBCs. According to the derivation formula, corresponding weight of RBC preservation solution was added to obtain 0.7~0.8 hematocrit concentrated washed RBCs. Routine blood test data were statistically analyzed by single-sample t test, and P<0.05 was considered statistically significant. Qualified Rh-negative/ O-type 0.7~0.8 hematocrit concentrated RBCs within expiry date were used in clinical intrauterine blood transfusion. 【Results】 The hematocrit of concentrated washing RBCs prepared by the new approach could reach 0.7~0.8. The RBCs count (8.389 ±0.808)×1 012/ L and hemoglobin content(233.730±15.498)g/L were higher while the erythrocyte count (0.732±0.469)×109 /L and platelets count(26.000±26.276)×109/L were lower than the normal values of adults. The mean erythrocyte volume(fL), hemoglobin content(pg) and concentration(g/L )were 88.123±6.359, 30.004±2.809 and 339.980±11.865, respectively, which were normal values of adults. Fetal anemia was significantly improved and the prognosis was good after intrauterine blood transfusion. 【Conclusion】 The 0.7~0.8 hematocrit concentrated washed RBCs prepared by the new approach is consistent with the special blood requirements during fetal anaemia transfusion, meets the clinical treatment standards, and can be applied in clinical.

Perinatal Outcome After Intrauterine Transfusion in Rh Isoimmunized Mothers.

OBJECTIVE: The objective of the study was to assess the fetal outcome after receiving intrauterine transfusion (IUT) in Rh-isoimmunized pregnancy in a tertiary care center. STUDY DESIGN: This was a retrospective observational descriptive study in which all Rh-negative gravidas with isoimmunization warranting IUTs (40 patients) were analyzed during the period from January 1, 2010 to October 31, 2015. Primary outcome variables were fetal outcomes and procedural-related factors. RESULTS: Forty pregnancies (13-hydropic, 27-non-hydropic) required 74 IUTs. IUT was performed at gestational age of 15.4-33 weeks when indicated. The amount of blood transfused ranged from 4 to 110 ml. There were two sudden intrauterine fetal deaths during the procedure, four post-procedure intrauterine fetal deaths in fetuses with severe hydrops, and three neonatal deaths. The overall survival rate was found to be 77.5%. CONCLUSION: IUT was found to be an effective therapy in correcting anemia in fetuses of Rh isoimmunized mothers. Early diagnosis of fetal anemia and intrauterine blood transfusion by an experienced fetal medicine specialist is very important for the perinatal outcome.

Magnetic Resonance Imaging: A New Tool to Optimize the Prediction of Fetal Anemia?

INTRODUCTION: The false-positive rate in the prediction of fetal anemia is 10-15%. We investigated if a new, noninvasive MRI method used as a supplement to ultrasound could improve the prediction. METHODS: Fetuses suspected of anemia and controls were scanned in a 1.5-tesla MRI scanner 1-4 times during pregnancy. Cases were scanned before and after intrauterine blood transfusion with a T1-mapping MRI sequence in a cross-section of the umbilical vein. RESULTS: Inclusion of 8 cases and 11 controls resulted in 10 case scans (2 cases were included twice) and 33 control scans. In controls, the T1 relaxation time was 1,005-1,391 ms; in cases with severe anemia, 1,505-1,595 ms, moderate anemia 1,503-1,525 ms, and no/mild anemia 1,245-1,410 ms. After blood transfusions, values dropped to 1,123-1,288 ms. The mean value in moderate and severe anemic cases was 275 ms higher than in controls (95% CI 210-341 ms, p < 0.0001), and after blood transfusion it was comparable to controls (3 ms, 95% CI -62 to 68 ms, p = 0.934). A 1,450-ms cut-off would have identified all cases in need of blood transfusion with no false-positive cases. CONCLUSIONS: Our findings indicate a potential for this new MRI method to improve the prediction of fetal anemia as a supplement to ultrasound.

Fetal anemia: Diagnosis and management.

Fetal anemia has been known for many years as a dangerous complication of pregnancy. Its most common causes are maternal alloimmunization and parvovirus B19 infection, although it can be associated with many different pathological conditions including fetal aneuploidies, vascular tumors, and arteriovenous malformations of the fetus or placenta and inherited conditions such as alpha-thalassemia or genetic metabolic disorders. Doppler ultrasonographic assessment of the peak velocity of systolic blood flow in the middle cerebral artery for the diagnosis of fetal anemia and intravascular intrauterine transfusion for its treatment are the current practice standards. Live birth rates as high as 95% have been reported in recent years. The additional role of intravenous immunoglobulin therapy and the long-term consequences of the condition are the subjects of active ongoing research.

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.

Predicting anti-Kell-mediated hemolytic disease of the fetus and newborn: diagnostic accuracy of laboratory management.

BACKGROUND: There is controversy on critical cut-off values of laboratory testing to select pregnancies at increased risk for anti-Kell-mediated hemolytic disease of the fetus and newborn. Without early detection and treatment, anti-Kell-mediated hemolytic disease of the fetus and newborn may result in progressive fetal anemia, fetal hydrops, asphyxia, and perinatal death. OBJECTIVE: We aimed to determine the value of repeated anti-Kell titer determination and biological activity measurement using the antibody-dependent cellular cytotoxicity test determination in the management of pregnancies at risk for anti-Kell-mediated hemolytic disease of the fetus and newborn. STUDY DESIGN: This was a retrospective cohort study of pregnancies with anti-Kell and a Kell-positive fetus, identified from January 1999 through April 2015. Laboratory test results and clinical outcome were collected from the Dutch nationwide screening program and the national reference center for fetal therapy in The Netherlands, the Leiden University Medical Center. Diagnostic accuracy was measured (receiver operating characteristic curves, sensitivity, specificity, positive and negative predictive values) for anti-Kell titers and antibody-dependent cellular cytotoxicity test. The relationship between the titer and antibody-dependent cellular cytotoxicity measurements and the 2 foregoing measurements were computed with a Pearson product-moment correlation coefficient. RESULTS: In a 16-year unselected cohort, representing screening results of 3.2 million pregnancies resulting in live births in The Netherlands, we identified 1026 Kell-immunized pregnancies. In all, 93 pregnant women had anti-Kell and a Kell-positive child, without other red cell alloantibodies. In all, 49 children (53%) needed intrauterine or postnatal transfusion therapy. The first anti-Kell titer showed already a high diagnostic accuracy with an area under the curve of 91%. The optimal cut-off point for the titer was 4 (sensitivity 100%; 95% confidence interval, 91-100), specificity 27% (95% confidence interval, 15-43), and positive predictive value 60% (49-71%). The antibody-dependent cellular cytotoxicity test was not informative to select high-risk pregnancies. Linear regression showed no significant change during pregnancy, when antibody titer and antibody-dependent cellular cytotoxicity test results were compared with every 2 foregoing measurements (P < .0001). CONCLUSION: Early determination of the anti-Kell titer is sufficient to select pregnancies at increased risk for hemolytic disease of the fetus and newborn with need for transfusion therapy. If the Kell status of the fetus is known to be positive, a titer of ≥4 can be used to target intensive clinical monitoring.

Postponing Early intrauterine Transfusion with Intravenous immunoglobulin Treatment; the PETIT study on severe hemolytic disease of the fetus and newborn.

BACKGROUND: Intrauterine transfusion for severe alloimmunization in pregnancy performed <20 weeks' gestation is associated with a higher fetal death rate. Intravenous immunoglobulins may prevent hemolysis and could therefore be a noninvasive alternative for early transfusions. OBJECTIVE: We evaluated whether maternal treatment with intravenous immunoglobulins defers the development of severe fetal anemia and its consequences in a retrospective cohort to which 12 fetal therapy centers contributed. STUDY DESIGN: We included consecutive pregnancies of alloimmunized women with a history of severe hemolytic disease and by propensity analysis compared index pregnancies treated with intravenous immunoglobulins (n = 24) with pregnancies managed without intravenous immunoglobulins (n = 28). RESULTS: In index pregnancies with intravenous immunoglobulin treatment, fetal anemia developed on average 15 days later compared to previous pregnancies (8% less often <20 weeks' gestation). In pregnancies without intravenous immunoglobulin treatment anemia developed 9 days earlier compared to previous pregnancies (10% more <20 weeks), an adjusted 4-day between-group difference in favor of the immunoglobulin group (95% confidence interval, -10 to +18; P = .564). In the subcohort in which immunoglobulin treatment was started <13 weeks, anemia developed 25 days later and 31% less <20 weeks' gestation (54% compared to 23%) than in the previous pregnancy. Fetal hydrops occurred in 4% of immunoglobulin-treated pregnancies and in 24% of those without intravenous immunoglobulin treatment (odds ratio, 0.03; 95% confidence interval, 0-0.5; P = .011). Exchange transfusions were given to 9% of neonates born from pregnancies with and in 37% without immunoglobulin treatment (odds ratio, 0.1; 95% confidence interval, 0-0.5; P = .009). CONCLUSION: Intravenous immunoglobulin treatment in mothers pregnant with a fetus at risk for hemolytic disease seems to have a potential clinically relevant, beneficial effect on the course and severity of the disease. Confirmation in a multicenter randomized trial is needed.