An ongoing problem: Rhesus hemolytic disease of the newborn - A decade of experience in a single centre.

BACKGROUND: The objectives were to evaluate the descriptive features of newborns with a diagnosis of Rhesus (Rh) hemolytic disease, to determine the morbidity and mortality rates, to evaluate the treatment methods and the factors affecting treatment requirements and clinical outcomes during a ten-year period at a tertiary center. METHODS: Newborn infants who had a positive direct Coombs test and/or had a history of intrauterine transfusion (IUT) due to Rh hemolytic disease were included. The data regarding the prenatal, natal and postnatal periods were collected from hospital records. RESULTS: A total of 260 neonates were included of which 51.2% were female. The mean ± standard deviation gestational age was 36.9 ± 2.7 weeks. The rate of preterm birth was 41.2%. Of 257 mothers whose obstetric medical history could be accessed, 87.2% were multigravida, whereas 76.3% were multiparous. Among mothers who had a reliable history of anti-D immunoglobulin prophylaxis (n=191), 51.3% had not received anti-D immunoglobulin prophylaxis in their previous pregnancies. The antenatal transfusion rate was 31.7% and the frequency of hydrops fetalis was 8.8%. While combined exchange transfusion (ET) and phototherapy (PT) was performed in 15.4% of the babies, the majority either needed phototherapy only (51.1%) or no treatment (33.5%). The mortality rate was 3.8 % (n = 10), and nine babies out of these 10 were those with severe hydrops fetalis. CONCLUSION: This study showed that Rh hemolytic disease is still a major problem in developing countries. Multiple comorbidities may occur in addition to life threatening complications, including hydrops fetalis, anemia and severe hyperbilirubinemia. High rates of multiparity and low rates of anti-D immunoglobulin prophylaxis are potential barriers for the eradication of the disease. It should be remembered that Rh hemolytic disease is a preventable disease in the presence of appropriate antenatal follow-up and care facilities.

Induced Abortion and the Risk of Rh Sensitization.

Importance: While population-level data suggest Rh immunoglobulin is unnecessary before 12 weeks' gestation, clinical evidence is limited. Thus, guidelines vary, creating confusion surrounding risks and benefits of Rh testing and treatment. As abortion care in traditional clinical settings becomes harder to access, many people are choosing to self-manage and need to know if ancillary blood type testing is necessary. Objective: To determine how frequently maternal exposure to fetal red blood cells (fRBCs) exceeds the most conservative published threshold for Rh sensitization in induced first-trimester abortion. Design, Setting, and Participants: Multicenter, observational, prospective cohort study using high-throughput flow cytometry to detect circulating fRBCs in paired maternal blood samples before and after induced first-trimester abortion (medication or procedural). Individuals undergoing induced first-trimester abortion before 12 weeks 0 days' gestation were included. Paired blood samples were available from 506 participants who underwent either medical (n = 319 [63.0%]) or procedural (n = 187 [37.0%]) abortion. Exposure: Induced first-trimester abortion. Main Outcomes and Measures: The primary outcome was the proportion of participants with fRBC counts above the sensitization threshold (125 fRBCs/5 million total RBCs) after induced first-trimester abortion. Results: Among the 506 participants, the mean (SD) age was 27.4 (5.5) years, 313 (61.9%) were Black, and 123 (24.3%) were White. Three of the 506 participants had elevated fRBC counts at baseline; 1 of these patients had an elevated fRBC count following the abortion (0.2% [95% CI, 0%-0.93%]). No other participants had elevated fRBC counts above the sensitization threshold after induced first-trimester abortion. The median change from baseline was 0 fRBCs, with upper 95th and 99th percentiles of 24 and 35.6 fRBCs, respectively. Although there was a strong association between the preabortion and postabortion fRBC counts, no other baseline characteristic was significantly associated with postabortion fRBC count. Conclusions and Relevance: Induced first-trimester abortion is not a risk factor for Rh sensitization, indicating that Rh testing and treatment are unnecessary before 12 weeks' gestation. This evidence may be used to inform international guidelines for Rh immunoglobulin administration following first-trimester induced abortion.

Fetal and Neonatal Reticulocyte Count Response to Intrauterine Transfusion for the Treatment of Red Blood Cell Alloimmunization.

Management of hemolytic disease of the fetus and newborn relies on monitoring of maternal antibody titers, fetal ultrasound, and fetal middle cerebral artery peak systolic velocity studies and is generally treated by intrauterine transfusion (IUT). Few studies have explored fetal and neonate physiological responses to IUT. Our objective was to examine fetal erythropoietic response and to examine neonatal erythropoietic effects after treatment. Thirty-six patients treated from 2005 to 2015 were identified retroactively. The time course of treatment, including gestational age and number of IUT, and timing of delivery were reviewed. Fetal reticulocyte count and neonatal hemoglobin and reticulocyte counts were analyzed for each IUT. For each gestational week, reticulocyte count decreased by ∼8.6% (95% confidence interval [CI]: 5.3-12.0). In the neonatal period, there was significant correlation between hemoglobin at birth and number of transfusions (Spearman correlation 0.473, 95% CI: 0.113-0.715, P =0.01) as well as reticulocyte count at birth and number of transfusions (Spearman correlation: 0.393, 95% CI: 0.058-0.642, P =0.02). IUT appears to have a direct and measurable effect on fetal reticulocyte production which persists in neonates.

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.

Perinatal outcomes and survival predictors of severe red-cell alloimmunization treated by intrauterine transfusion.

OBJECTIVE: To evaluate perinatal survival rates and predictors in severely anemic fetuses that underwent intrauterine transfusion (IUT). METHOD: This was a retrospective study of both Turkish and Syrian patients who underwent IUT for fetal anemia due to Rh alloimmunization between 2015 and 2019. The association between pretransfusion factors and perinatal survival was evaluated by multivariate logistic regression. Receiver operating characteristics (ROC) curves were used to identify the level of fetal hemoglobin deficits that predict perinatal survival. RESULTS: Eighty-seven IUTs were performed in 42 pregnancies. Approximately 75% of fetuses were severely anemic and the overall perinatal survival rate was 50%. The survival rate was better in Syrian refugees compared to Turkish patients (71.4% vs. 39.3%, p < 0.05). In univariate analysis, hydrops presence (odds ratio [OR] = 0.2; 95% confidence interval [CI] = 0.05-0.7; p < 0.05), first IUT week (OR = 1.4; 95% CI = 1.1-1.8; p < 0.05), pretransfusion hemoglobin level (OR = 1.99; 95% CI = 1.22-3.27; p < 0.05), hemoglobin deficit (OR = 0.5; 95% CI = 0.3-0.8; p < 0.05), and birth week (OR = 2.3; 95% CI = 1.3-3.9; p < 0.05) were associated with survival. However in a multivariate analysis, only hemoglobin deficit (OR = 0.47; 95% CI = 0.22-0.99; p < 0.05) and birth week (OR = 3.3; 95% CI = 1.1-10.3; p < 0.05) were found to be associated with survival. On ROC analysis, a hemoglobin deficit of ≤6.25 g/dl showed a sensitivity of 0.95 and specificity of 0.62 for predicting perinatal survival. CONCLUSION: Despite the improvement in the treatment of fetal anemia, perinatal survival rate remains extremely low in severely anemic cases. Among pretransfusion factors, hemoglobin deficit seemed to be most important in predicting survival during fetal anemia.

Hemolytic disease of the fetus and newborn due to Rh(D) incompatibility: A preventable disease that still produces significant morbidity and mortality in children.

In the mid-20th century, Hemolytic Disease of the Fetus and Newborn, caused by maternal alloimmunization to the Rh(D) blood group antigen expressed by fetal red blood cells (i.e., "Rh disease"), was a major cause of fetal and neonatal morbidity and mortality. However, with the regulatory approval, in 1968, of IgG anti-Rh(D) immunoprophylaxis to prevent maternal sensitization, the prospect of eradicating Rh disease was at hand. Indeed, the combination of antenatal and post-partum immunoprophylaxis is ~99% effective at preventing maternal sensitization to Rh(D). To investigate global compliance with this therapeutic intervention, we used an epidemiological approach to estimate the current annual number of pregnancies worldwide involving an Rh(D)-negative mother and an Rh(D)-positive fetus. The annual number of doses of anti-Rh(D) IgG required for successful immunoprophylaxis for these cases was then calculated and compared with an estimate of the annual number of doses of anti-Rh(D) produced and provided worldwide. Our results suggest that ~50% of the women around the world who require this type of immunoprophylaxis do not receive it, presumably due to a lack of awareness, availability, and/or affordability, thereby putting hundreds of thousands of fetuses and neonates at risk for Rh disease each year. The global failure to provide this generally acknowledged standard-of-care to prevent Rh disease, even 50 years after its availability, contributes to an enormous, continuing burden of fetal and neonatal disease and provides a critically important challenge to the international health care system.

Red cell alloimmunization: A 2020 update.

Management of maternal red cell alloimmunization has been revolutionized over the last 60 years. Advances in the prevention, screening, diagnosis, and treatment of alloimmune-induced fetal anemia make this condition an exemplar for contemporary practice in fetal therapy. Since survival is now an expectation, attention has turned to optimization of long-term outcomes following an alloimmunized pregnancy. In this review, the current management of red cell alloimmunization is described. Current research and future directions are discussed with particular emphasis on later life outcomes after alloimmune fetal anemia.

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.

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.

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.

Management of red blood cell alloimmunization in pregnancy.

The main cause of fetal anemia is maternal red blood cell alloimmunization (AI). The search of maternal antibodies by indirect antiglobulin test allows screening for AI during pregnancy. In case of AI, fetal genotyping (for Rh-D, Rh-c, Rh-E and Kell), quantification (for anti-rhesus antibodies) and antibody titration, as well as ultrasound monitoring, are performed. This surveillance aims at screening for severe anemia before hydrops fetalis occurs. Management of severe anemia is based on intrauterine transfusion (IUT) or labor induction depending on gestational age. After intrauterine transfusion, follow-up will focus on detecting recurrence of anemia and detecting fetal brain injury. With IUT, survival of fetuses with alloimmunization is greater than 90% but 4.8% of children with at least one IUT have neurodevelopmental impairment.

ACOG Practice Bulletin No. 192 Summary: Management of Alloimmunization During Pregnancy.

When any fetal blood group factor inherited from the father is not possessed by the mother, antepartum or intrapartum fetal-maternal bleeding may stimulate an immune reaction in the mother. Maternal immune reactions also can occur from blood product transfusion. The formation of maternal antibodies, or "alloimmunization," may lead to various degrees of transplacental passage of these antibodies into the fetal circulation. Depending on the degree of antigenicity and the amount and type of antibodies involved, this transplacental passage may lead to hemolytic disease in the fetus and neonate. Undiagnosed and untreated, alloimmunization can lead to significant perinatal morbidity and mortality. Advances in Doppler ultrasonography have led to the development of noninvasive methods of management of alloimmunization in pregnant women. Together with more established protocols, Doppler ultrasound evaluation may allow for a more thorough and less invasive workup with fewer risks to the mother and fetus. Prevention of alloimmunization is addressed in another Practice Bulletin ().

ACOG Practice Bulletin No. 192: Management of Alloimmunization During Pregnancy.

When any fetal blood group factor inherited from the father is not possessed by the mother, antepartum or intrapartum fetal-maternal bleeding may stimulate an immune reaction in the mother. Maternal immune reactions also can occur from blood product transfusion. The formation of maternal antibodies, or "alloimmunization," may lead to various degrees of transplacental passage of these antibodies into the fetal circulation. Depending on the degree of antigenicity and the amount and type of antibodies involved, this transplacental passage may lead to hemolytic disease in the fetus and neonate. Undiagnosed and untreated, alloimmunization can lead to significant perinatal morbidity and mortality. Advances in Doppler ultrasonography have led to the development of noninvasive methods of management of alloimmunization in pregnant women. Together with more established protocols, Doppler ultrasound evaluation may allow for a more thorough and less invasive workup with fewer risks to the mother and fetus. Prevention of alloimmunization is addressed in another Practice Bulletin ().

Successful management of a severe anti-M alloimmunization during pregnancy.

We report the successful outcome of a patient with anti-M antibodies with a previous history of severe hemolysis of erythrocytes. Serial plasma exchange from the first trimester combined with ultrasound monitoring of the fetal middle cerebral artery blood velocity was implemented. This management allowed a favorable pregnancy outcome of an infant born by an elective caesarean section at 32 weeks 6/7 with a normal Apgar score at 8/9/10. The other therapeutic alternatives such as intravenous immunoglobulin and in utero fetal blood transfusions are discussed.

No. 343-Routine Non-invasive Prenatal Prediction of Fetal RHD Genotype in Canada: The Time is Here.

The optimal management of the D-negative pregnant woman is now based on the non-invasive antenatal prediction of fetal D-blood group by cell-free DNA (cfDNA) in maternal plasma, with targeted prophylaxis for women carrying RHD-positive fetuses. This provides the optimal care for D-negative pregnant women and has been adopted as the standard approach in a growing number of countries around the world. This paper is the result of a consensus meeting of the Canadian National Rh Working Group, an interdisciplinary group formed to review the current status of fetal RHD genotyping based on cfDNA in Canada. The group, in collaboration with the SOGC Genetics committee, reviewed the benefits and challenges of implementing RHD genotyping with targeted prophylaxis in the context of the existing routine antenatal anti D prophylaxis program in Canada. The following summary statements and recommendations are based on this review. SUMMARY STATEMENTS: RECOMMENDATIONS.

Long-term cardiovascular outcome following fetal anaemia and intrauterine transfusion: a cohort study.

OBJECTIVE: To compare long-term cardiovascular outcomes in survivors of fetal anaemia and intrauterine transfusion with those of non-anaemic siblings. DESIGN: Retrospective cohort study. SETTING: Auckland, New Zealand. PARTICIPANTS: Adults who received intrauterine transfusion for anaemia due to rhesus disease (exposed) and their unexposed sibling(s). EXPOSURE: Fetal anaemia requiring intrauterine transfusion. MAIN OUTCOME MEASURES: Anthropometry, blood pressure, lipids, heart rate variability and cardiac MRI, including myocardial perfusion. RESULTS: Exposed participants (n=95) were younger than unexposed (n=92, mean±SD 33.7±9.3 vs 40.1±10.9 years) and born at earlier gestation (34.3±1.7 vs 39.5±2.1 weeks). Exposed participants had smaller left ventricular volumes (end-diastolic volume/body surface area, difference between adjusted means -6.1, 95% CI -9.7 to -2.4 mL/m2), increased relative left ventricular wall thickness (difference between adjusted means 0.007, 95% CI 0.001 to 0.012 mm.m2/mL) and decreased myocardial perfusion at rest (ratio of geometric means 0.86, 95% CI 0.80 to 0.94). Exposed participants also had increased low frequency-to-high frequency ratio on assessment of heart rate variability (ratio of geometric means 1.53, 95% CI 1.04 to 2.25) and reduced high-density lipoprotein concentration (difference between adjusted means -0.12, 95% CI -0.24 to 0.00 mmol/L). CONCLUSIONS: This study provides the first evidence in humans that cardiovascular development is altered following exposure to fetal anaemia and intrauterine transfusion, with persistence of these changes into adulthood potentially indicating increased risk of cardiovascular disease. These findings are relevant to the long-term health of intrauterine transfusion recipients, and may potentially also have implications for adults born preterm who were exposed to anaemia at a similar postconceptual age.

Sensitivity of fetal RHD screening for safe guidance of targeted anti-D immunoglobulin prophylaxis: prospective cohort study of a nationwide programme in the Netherlands.

OBJECTIVE:  To determine the accuracy of non-invasive fetal testing for the RHD gene in week 27 of pregnancy as part of an antenatal screening programme to restrict anti-D immunoglobulin use to women carrying a child positive for RHD DESIGN:  Prospectively monitoring of fetal RHD testing accuracy compared with serological cord blood typing on introduction of the test. Fetal RHD testing was performed with a duplex real time quantitative polymerase chain reaction, with cell-free fetal DNA isolated from 1 mL of maternal plasma The study period was between 4 July 2011 and 7 October 2012. The proportion of women participating in screening was determined. SETTING:  Nationwide screening programme, the Netherlands. Tests are performed in a centralised setting. PARTICIPANTS:  25 789 RhD negative pregnant women. MAIN OUTCOME MEASURES:  Sensitivity, specificity, false negative rate, and false positive rate of fetal RHD testing compared with serological cord blood typing; proportion of technical failures; and compliance to the screening programme. RESULTS:  A fetal RHD test result and serological cord blood result were available for 25 789 pregnancies. Sensitivity for detection of fetal RHD was 99.94% (95% confidence interval 99.89% to 99.97%) and specificity was 97.74% (97.43% to 98.02%). Nine false negative results for fetal RHD testing were registered (0.03%, 95% confidence interval 0.01% to 0.06%). In two cases these were due to technical failures. False positive fetal RHD testing results were registered for 225 samples (0.87%, 0.76% to 0.99%). Weak RhD expression was shown in 22 of these cases, justifying anti-D immunoglobulin use. The negative and positive predictive values were 99.91% (95% confidence interval 99.82% to 99.95%) and 98.60% (98.40% to 98.77%), respectively. More than 98% of the women participated in the screening programme. CONCLUSIONS:  Fetal RHD testing in week 27 of pregnancy as part of a national antenatal screening programme is highly reliable and can be used to target both antenatal and postnatal anti-D immunoglobulin use.