hemolytic disease of the newborn case presentation

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Hemolytic disease of the newborn.

Victoria Hall ; Indirapriya Darshini Avulakunta .

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Last Update: November 22, 2022 .

• Continuing Education Activity

Hemolytic disease of the fetus and newborn is a red blood cell mismatch between mothers and their fetuses that can cause significant morbidity and mortality. Fortunately, fatal consequences from this disorder have become rare with the appropriate use of immunoprophylaxis. However, to avoid the fatal consequences of this disorder, prompt recognition and treatment are vital. This activity reviews the evaluation, treatment, and prevention of hemolytic disease of the fetus and newborn by the interprofessional team.

• Describe the etiology and epidemiology of hemolytic disease of the fetus and newborn.
• Review the pathophysiology of hemolytic disease of the fetus and newborn.
• Outline the management of hemolytic disease of the fetus and newborn.
• Summarize interprofessional team strategies for improving care coordination and communication to advance the care of hemolytic disease of the fetus and newborn and improve outcomes.
• Introduction

Hemolytic disease of the fetus and newborn (HDFN) is an immune-mediated red blood cell (RBC) disorder in which maternal antibodies attack fetal or newborn RBCs. [1] [2]  HDFN can cause significant morbidity and mortality, especially in limited healthcare resource settings. Effects of HDFN range from mild anemia to hydrops fetalis in the fetus and hyperbilirubinemia and kernicterus in the newborn. [1] [3]  Through early detection, management, and prevention of this disease, the incidence, and prevalence of HDFN have exponentially decreased in the past 50 years. [1]

There are two main mechanisms by which maternal antibodies target fetal or newborn RBC antigens:

• ABO incompatibility
• Fetomaternal hemorrhage

ABO incompatibility is a congenital, inherent mismatch between maternal and fetal blood types. [4]  Conversely, alloimmunization due to fetomaternal hemorrhage (FMH) is an acquired immune-mediated mechanism that typically affects subsequent pregnancies rather than the pregnancy in which the FMH happens. [2] [5]

• Epidemiology

Hemolytic disease of the fetus and newborn was first described by Dr. Louis K. Diamond in 1932 when he wrote about erythroblastosis fetalis in the newborn based on peripheral smears. [6]  Rhesus D-negative (RhD) immunoprophylaxis was first introduced in 1968, which dropped the incidence of HDFN from 1% of all newborns worldwide (with 50% mortality) to 0.5%. [1] The incidence of HDFN decreased even further to 0.1% with the administration of antepartum RhD immunoprophylaxis. [2]  However, despite adequate RhD immunoprophylaxis, an estimated 1 to 3 in 1000 Rh-negative women still develop alloimmunization today. Thus it is important to stay vigilant for the development of HDFN. [1]

Rh incompatibility varies by race, ethnicity, and risk factors. The Rh-negative blood type is most predominant in white races (15%) compared to African Americans (5% to 8%) or Asians and Native Americans (1% to 2%). Among white women, an Rh-negative woman has an 85% chance of mating with an Rh-positive man. [1]  This frequently occurring Rh-incompatibility increases the risk of HDFN with any FMH event.

As little as 0.1 mL of fetal blood entering maternal circulation is sufficient to cause alloimmunization. [7]  In fact, 15 to 50% of gestations have sufficient fetomaternal hemorrhage to cause alloimmunization, and only 1 to 2% of all Rh alloimmunization is caused by antepartum FMH. [7]  As such, it is important to consider HDFN at all stages of the pregnancy where FMH may occur.

• Pathophysiology

As mentioned, there are two mechanisms causing hemolytic disease of the fetus and newborn. First, the fetomaternal pair can have inherent ABO incompatibility, which occurs in 15 to 25% of pregnancies. [8]  Only about 1% of those pairs, those with high IgG titers, will develop HDFN due to ABO incompatibility. [8]  In ABO incompatibility, naturally occurring antigens against A or B blood types are present in mothers with O blood type. If the mother's fetus has an A or B (or AB) blood type, maternal anti-A and/or anti-B antibodies, respectively, will attack the foreign blood type of the fetus. The anti-A and anti-B antibodies are IgG, which can cross the placenta and affect the developing fetus. [9]  Compared with FMH, ABO incompatibility generally causes a less severe form of HDFN. Postulated theories for this include fetal RBCs express less ABO blood group antigens than adult levels and that ABO blood group antigens are expressed by many tissues, which reduces the chance that antibodies specifically target the antigens on fetal RBCs. [4]

The second mechanism most commonly causing HDFN is through fetomaternal hemorrhage (FMH), where maternal antibodies develop after exposure to fetal blood. When fetal RBCs enter the maternal blood circulation, maternal antibodies can develop to an antigen presented on the fetal RBC surface. The most common antigen involved in this mechanism is the Rhesus D antigen. [10]  It is estimated that 1.5 to 2.5% of obstetric patients will develop antibodies to other "minor" antigens. While most of these cases of alloimmunization do not cause significant hemolytic disease of the newborn, some can cause severe anemia at low titer thresholds. Antibodies against the antigens of the Kell blood group, for example, are associated with an increased risk of severe anemia and/or death of the fetus. These patients should be monitored very closely throughout the pregnancy. [3] [7]

Antigens in fetal blood that are foreign to maternal blood are inherited from paternal genes. For example, an Rh-negative woman can have an Rh-positive fetus due to her partner being Rh-positive. Antibodies that develop due to FMH put subsequent pregnancies at risk for HDFN as the first antibodies to develop are of IgM type, which cannot cross the placenta. In subsequent encounters with the Rh-D antigen, maternal antibodies rapidly develop IgG antibodies, which do cross the placenta. [11]

As infant RBCs are attacked and broken down, infants develop hemolytic anemia. The breakdown of heme leads to bilirubin, which is removed by the placenta in utero. At birth, the liver begins processing the bilirubin. Indirect bilirubin, or unconjugated bilirubin, is conjugated to direct bilirubin using the enzyme uridine diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase). This conjugated bilirubin is excreted in bile, where it ultimately will be excreted in feces and urine.

In infants, especially preterm infants, liver processing is less efficient, which often leads to natural physiologic jaundice. [12]  With excess breakdown products from HDFN, these immature processing mechanisms are overwhelmed, and the resulting hyperbilirubinemia can be prominent. The accumulation of unconjugated bilirubin can lead to neurologic dysfunction as the unbound bilirubin crosses the blood-brain barrier and deposits in the brain of the developing newborn. [13]  Prompt recognition and treatment of hyperbilirubinemia and HDFN are paramount to avoiding long-term neurologic dysfunction in these infants.

• History and Physical

An in-depth history can be essential in raising suspicion for hemolytic disease of the fetus and newborn. Emphasis should be placed on identifying any events that may have led to fetomaternal hemorrhage. These include previous pregnancies with HDFN or hydrops fetalis, miscarriages, ectopic pregnancies, early pregnancy terminations, blood transfusions in the mother, chorionic villous sampling, amniocentesis, or documentation of bleeding in pregnancy. [7]

Early in the first trimester, blood typing should be done on all pregnant women. Those with blood type O naturally express antibodies to A and B blood types; thus, they should be monitored for the development of HDFN, especially at delivery and directly postpartum. The antibodies expressed in mothers with O blood type are typically immunoglobulin G (IgG) and can cross the placenta. Conversely, mothers with blood type A have antibodies against blood type B, which are predominantly immunoglobulin M (IgM) and do not cross the placenta. [8]  It is generally standard practice to check the blood types of infants born to mothers with blood type O at birth, whereas blood types of infants whose mothers have blood types A, B, or AB may not be checked (if the Rhesus factor is positive).

The main signs of hemolytic disease in the newborn (HDN) are anemia and hyperbilirubinemia, which may present as lethargy, jaundice, conjunctival icterus, pallor, hepatosplenomegaly, tachycardia or bradycardia, increased oxygen requirement, and/or apnea. [9] [13]

Hemolytic disease of the fetus and newborn should be considered in the differential diagnosis of newborns with jaundice/hyperbilirubinemia and certainly in the case of neonatal anemia. Diagnosis of HDFN can be made by identifying the presence of maternal RBC antibodies (agglutination in an indirect antibody test) and/or a positive direct antibody test (DAT) in the infant's serum. [4]  If a pregnant woman is identified to have alloimmunization, the first step in further evaluation is to determine the paternal RBC antigen status. If positive, the next step is to identify the fetal blood type, typically done through amniocentesis. [7]

According to the American Academy of Pediatrics (AAP), "if a mother has not had prenatal blood grouping or is Rh-negative, a direct antibody test (or Coombs' test), blood type, and an Rh (D) type on the infant's (cord) blood are strongly recommended." [13]

• Treatment / Management

If hemolytic disease of the fetus and newborn is identified or suspected in utero, a consult with maternal-fetal medicine should be placed as early as possible in the pregnancy. Affected pregnancies can be managed by monitoring antibody titers, and fetal middle cerebral artery velocities, intrauterine transfusions, and possibly early delivery, as infants with severe anemia may not tolerate term labor well. [7]

Hemolytic disease of the newborn is managed by treating hyperbilirubinemia with phototherapy and exchange transfusions if needed. Routine universal screening with transcutaneous bilirubin (TcB) often occurs at 24 hours of life, but screening should be conducted as soon as hyperbilirubinemia is suspected. An elevated TcB should always be verified with a serum total bilirubin (TB). The hour-specific Bhutani nomogram is then used to risk stratify the amount of bilirubin in the infant's blood. [13]  This nomogram provides a recommended threshold for starting phototherapy versus early transfusions depending on the infant's risk level.

Phototherapy was introduced in the 1970s and has become the mainstay of hyperbilirubinemia management in newborns. Photo isomerization causes the transformation of bilirubin into a water-soluble isomer that can then be excreted by the kidneys and stool without the need for processing in the liver. The main determinants of phototherapy efficacy are the wavelength of light used, the intensity of that light, the total light dose (time exposed and surface area exposed), and the threshold at which phototherapy is initiated. The AAP recommends the use of intensive phototherapy in HDFN. The optimal light used for phototherapy has a wavelength of 460-490nm. The light should be at a close distance (about 20cm above the infant), and double phototherapy has proven to be more efficacious than single. There is limited data on the efficacy of continuous versus intermittent phototherapy for infants >2000g. [1]  During the use of phototherapy, mothers should be encouraged to breastfeed their infants at timely intervals despite needing to remove them from phototherapy to do so.

An exchange transfusion may be needed for severely anemic newborns, which involves replacing infant RBCs with antigen-negative RBCs, thereby preventing further hemolysis. 5mL/kg aliquots are removed and replaced over several minutes for a total of 25-50mL/kg exchange of RBCs. Exchange transfusions are recommended by the AAP if total bilirubin levels remain above the transfusion threshold despite intensive phototherapy or if signs of bilirubin encephalopathy are present. If an exchange transfusion is being considered, an albumin level should be measured. Albumin of 3.0 g/dL or less is considered an independent risk factor for hyperbilirubinemia and lowers the phototherapy threshold. Without sufficient albumin to bind bilirubin, the amount of free, unconjugated bilirubin increases, thereby increasing the risk for kernicterus. [1]

Anemic infants may require blood transfusions with ABO-matched packed RBCs. If immediate transfusion is thought to be needed, O-type, Rh-negative blood that has been leukodepleted and irradiated should be available at delivery. [1]

Other treatment modalities have been considered but are still controversial. Intravenous immunoglobulin (IVIG) in the infant may block Fc receptors on macrophages, thereby decreasing the breakdown of antibody-coated RBCs. IVIG is recommended by the AAP if total serum bilirubin continues to rise despite intensive phototherapy or is within 2-3 mg/dL of the exchange transfusion level. Administration of IVIG to mothers prior to delivery has not been shown to be efficacious and is not currently recommended. Other agents such as albumin, phenobarbital, metalloporphyrins, zinc, clofibrate, and prebiotics have been studied as possible treatment options for hyperbilirubinemia, but none are currently recommended. [14]  In a recent randomized control trial of 70 infants with Rh-alloimmunization, delayed cord clamping was shown to improve anemia without increasing the incidence of adverse events. Delayed cord clamping had no significant impact, however, on the need for exchange transfusion or duration of phototherapy. [15]

• Differential Diagnosis

Hemolytic disease of the fetus and newborn should be included in the differential diagnosis of infants with early, severe, or prolonged jaundice and anemia. Other etiologies of jaundice and hyperbilirubinemia in the newborn include physiologic jaundice, prematurity, breast milk and breastfeeding jaundice, G6PD deficiency, thalassemia, sepsis, birth trauma, Gilbert syndrome, and hypothyroidism. [3]  The history and physical, as well as simple laboratory evaluation, as described above, can help differentiate these causes.

• Treatment Planning

The American Association of Blood Banks recommends repeat antibody screening prior to administration of Rh-D immunoprophylaxis (Rh-D IgG) at 28 weeks of gestation, postpartum, and in FMH events. [5]  In a network meta-analysis conducted in China, the most effective protocol for preventing maternal alloimmunization was the administration of Rh-D immunoprophylaxis at 28 and 34 gestational weeks in Rh-negative women. [16]  

The standard dose of anti-RhD administered in the second and third trimesters and postpartum, if needed, is 300mcg. If needed in the first trimester, the recommended dose is 150 mcg. A one-time dose of 300 mcg anti-RhD should prevent isoimmunization when 15mL or less of fetal RBCs (or 30mL of whole blood) enters maternal circulation. A rosette test is a qualitative test to assess potential FMH. If positive, the rosette test should be followed by the Kleihauer-Betke test to quantify the amount of fetomaternal blood mixing to then determine if additional doses of Rh-D immunoprophylaxis are needed. [10]

The overall prognosis of HDFN is good if identified and treated promptly. While permanent neurologic dysfunction may result from delays in care, this is now a rare occurrence with the advancements in monitoring as well as prophylaxis against HDFN.

• Complications

Acute bilirubin encephalopathy from the buildup of bilirubin in an infant's brain may manifest as hypotonia or poor suck reflex, which then progresses to irritability and hypertonia with retrocollis and opisthotonos. Long-term consequences of chronic bilirubin encephalopathy may lead to cerebral palsy, auditory dysfunction, paralysis of upward gaze, and permanent intellectual dysfunction. [13]  Thus, early recognition and treatment are imperative to prevent the detrimental progression of HDFN.

• Deterrence and Patient Education

Patient education regarding routine lab testing and Rh-D immunoprophylaxis in Rh-negative women is necessary to ensure possible FMH events are reported and appropriately treated in pregnant women. Additionally, parents of newborns can be educated on the signs and symptoms to be aware of hyperbilirubinemia to assist the interprofessional team in the early identification of possible HDFN cases.

• Enhancing Healthcare Team Outcomes

Enhancing interprofessional team outcomes for patients with hemolytic disease of the fetus and newborn requires close collaboration between both OB/GYN and pediatric providers, nurses, pharmacists, and blood bank personnel. With HDFN, there are two patients to consider at all times - the mother and the fetus/newborn. When HDFN is identified in utero, the delivery team should be well-versed and prepared ahead of time to identify signs and symptoms of HDFN, as these infants may need timely transfusions at birth. Pharmacists and providers must identify if and when Rh-D immunoprophylaxis is indicated to prevent future HDFN cases throughout the pregnancy. Through the development of Rh-D immunoprophylaxis and newborn work-up protocols, the incidence of HDFN has dramatically dropped in the past 50 years. Still, it will take continued interprofessional collaboration to ensure the incidence of HDFN remains low.

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Disclosure: Victoria Hall declares no relevant financial relationships with ineligible companies.

Disclosure: Indirapriya Darshini Avulakunta declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Hall V, Avulakunta ID. Hemolytic Disease of the Newborn. [Updated 2022 Nov 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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Epidemiology and pathophysiology

Fetal management, neonatal management, prevention (transfusion, rhig), correspondence, hemolytic disease of the fetus and newborn: managing the mother, fetus, and newborn.

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Meghan Delaney , Dana C. Matthews; Hemolytic disease of the fetus and newborn: managing the mother, fetus, and newborn. Hematology Am Soc Hematol Educ Program 2015; 2015 (1): 146–151. doi: https://doi.org/10.1182/asheducation-2015.1.146

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Hemolytic disease of the fetus and newborn (HDFN) affects 3/100 000 to 80/100 000 patients per year. It is due to maternal blood group antibodies that cause fetal red cell destruction and in some cases, marrow suppression. This process leads to fetal anemia, and in severe cases can progress to edema, ascites, heart failure, and death. Infants affected with HDFN can have hyperbilirubinemia in the acute phase and hyporegenerative anemia for weeks to months after birth. The diagnosis and management of pregnant women with HDFN is based on laboratory and radiographic monitoring. Fetuses with marked anemia may require intervention with intrauterine transfusion. HDFN due to RhD can be prevented by RhIg administration. Prevention for other causal blood group specificities is less studied.

Explain the fetal and infant clinical findings associated with hemolytic disease of the fetus and newborn (HDFN)

Describe the approach to pregnancy management when a mother has red cell alloimmunization

Discuss the prevention strategies for HDFN

Hemolytic disease of the fetus and newborn (HDFN) is rare condition that occurs when maternal red blood cell (RBC) or blood group antibodies cross the placenta during pregnancy and cause fetal red cell destruction. The fetal physiological consequences of severe anemia in the fetus can also lead to edema, ascites, hydrops, heart failure, and death. In less severe cases, the in utero red cell incompatibility can persist postnatally with neonatal anemia due to hemolysis, along with hyperbilirubinemia and erythropoietic suppression.

There are an estimated 3/100 000 to 80/100 000 cases of HDFN per year in the United States. 1   The maternal blood group antibodies that cause HDFN can be naturally occurring ABO antibodies (isohemagglutinins), or develop after exposure to foreign RBC; the latter are called blood group alloantibodies. For HDFN to occur, the fetus must be antigen positive (paternally inherited) and the mother must be antigen negative. Several studies have investigated the prevalence of red cell sensitization. In a large series of 22 102 females in the US, 254 (1.15%) of the women were found to have a red cell alloantibodies, of whom 18% had more than one alloantibody. 2   In the Netherlands, the prevalence of red cell alloantibodies detected in the first trimester was 1.2%. 3  

The most common cause of blood group incompatibility results from the ABO blood group system, with incompatibility present in up to 20% of infants. 4   However, because anti-ABO antibodies are predominantly IgM class, most are not effectively transported across the placenta. In addition, the A and B antigens are not well developed on fetal red blood cells. Together, this results in a low rate of clinically severe HDFN due to ABO compatibility, although the incidence of more mild disease varies from 1:150 to 1:3000, depending on the parameters used for the case definition, such as bilirubin levels or neonatal anemia. 1   Because maternal ABO antibodies are present without previous sensitization, HDFN due to ABO antibodies can occur in the first pregnancy and has a recurrence rate up to 87%. 1   It is most commonly seen in group O mothers with group A infants (European ancestry) or group B infants (African ancestry).

The most clinically significant forms of HDFN are caused by maternal blood group alloantibodies are of IgG1 and IgG subclasses, which cause hemolysis more effectively than other IgG subclasses. IgG1 and IgG3 are transported across the placenta by the Fc receptor from the second trimester onward. 5   Once in the fetal circulation, the antibody binds antigen-positive fetal red cells that are then cleared by the fetal spleen. Free hemoglobin is metabolized into bilirubin that is conjugated by the maternal liver. As anemia worsens, fetal hematopoiesis increases, termed “erythroblastosis fetalis” and organs involved in red blood cell synthesis (liver, spleen) may enlarge. In the most severe cases, portal hypertension and reduced hepatic synthesis of albumin leads to low plasma oncotic pressure, edema and ascites. “Hydrops fetalis” refers to the state of widespread effusions and associated high-output cardiac failure and death. 6   A large population-based study in Sweden found that the presence of maternal red cell antibodies was significantly associated with adverse outcomes, with a 1.4-2.4 relative risk of preterm delivery and a 1.5-2.6 relative risk of stillbirth in mothers with red cell allosensitization as compared to those without. 7  

After delivery, the passive blood group antibody can continue to affect neonatal red cells causing ongoing anemia until the maternal antibody is no longer present, which can be weeks to months after birth. In early neonatal anemia, bilirubin from red cell destruction can rise quickly because the fetal liver's metabolic machinery is not well developed. Very high levels of unconjugated bilirubin can lead to bilirubin encephalopathy, which clinically presents acutely as lethargy, and can include neurological and muscular manifestations, such as hypotonia, hypertonia, a weak suck, seizures, and/or coma. Chronic and permanent effects of kernicterus, which is permanent neuronal damage from hyperbilirubinemia, includes cerebral palsy, auditory dysfunction, intellectual, or other handicaps. 6   Infants may also enter a hypoproliferative phase of anemia due to erythropoietic marrow suppression from maternal antibody, as well as intrauterine transfusion, and simple transfusion ( Table 1 ). 8   Low erythropoietin production by the infant may also be contributory to low hemoglobin levels. 9   Late hemolysis can continue to cause low blood counts and elevated bilirubin.

Neonatal manifestations of HDFN anemia by time of onset

Hb indicates hemoglobin; RBC, red blood cell; and IUT, intrauterine transfusion.

Adapted from Rath et al with permission. 8  

Maternal alloimmunization results from exposure to foreign red blood cells through previous or current pregnancy, previous transfusions, or organ transplant. During pregnancy, there is spontaneous mixing between fetal and maternal circulation (fetal–maternal hemorrhage; FMH). The mixing increases throughout the pregnancy; 3%, 12%, and 45% in trimesters I, II, and III, respectively, although the amounts of fetal blood in the maternal circulation is generally very small. Hemolytic disease of the fetus and newborn due to red cell alloantibodies rarely occurs in first pregnancies because the highest risk for FMH is later in the pregnancy, especially at delivery, and new alloantibodies are more likely to be formed after delivery. Any physical perturbation of a fetus or placenta in utero also increases the risk of FMH, such as trauma, abortion, ectopic pregnancy, amniocentesis, or multiple pregnancy. 10   Once exposed, the maternal immune system may or may not respond to foreign red cell antigens. 11   The immune response to red cell antigens is complex and not fully understood. It is clear that the RhD antigen is the most potent immunogen of all of the red cell antigens; 85% of RhD-negative individuals will sensitize (form anti-D) after challenge with a 200 mL transfusion of red cells, although more recent data suggests this is far lower. 12   Although as little as 0.1 to 1 mL of RhD-positive red cells can stimulate antibody production, the volumes of FMH are generally small, which contributes to relatively low alloimmunization rates in pregnancy. Before Rh(D) immunoprophylaxis was implemented in 1968, 16% of ABO compatible D-negative mothers with D-positive infants developed anti-D antibody. However, a much lower amount (≤2%) developed anti-D in mother/fetus pairs that were ABO incompatible because of the ABO antibody mediated clearance of fetal red cells from the maternal circulation. 13  

Although RhD remains the most prevalent cause for HDFN due to allosensitization, other red cell antigens are known to be commonly etiologic ( Table 2 ). Other antibodies that have been less commonly reported include E, k, Kp a , Kp b , Ku, Ge, M, Js a , Js b , Jk a , Fy a , Fy b , S, s, and U. 4   A Dutch case-controlled study utilizing a national database of 900 pregnant women with RBC sensitization to non-RhD red cell antibodies enumerated the risk factors for maternal allosensitization. Factors found to be associated with red cell allosensitization in the women were previous major surgery, red cell or platelet transfusion, multiparity, having had a previous male child, and operative removal of the placenta. 14  

Red blood cell antibody specificity in female population studies

Number of samples with antibody per 1000 samples.

Adapted from Giefman-Holtzman et al. 2  

All pregnant women should have testing performed, including a blood type (ABO, RhD) and antibody detection test (indirect antiglobulin test) that detects IgG antibodies. 15   For patients with red cell sensitization, the antibody specificity is determined and initial risk stratification occurs. Certain blood group antibodies such as anti-I, -P1, -Le a , and -Le b , may be ignored because the corresponding (cognate) antigens are incompletely developed at birth, the antibodies are typically not IgG, and clinical experience has established the rarity of their causing HDFN. 4   Women with red blood cell sensitization to clinically significant red cell antigens (such as D, E, c, K, etc) are transitioned into a pathway of more intensive diagnostic testing and monitoring. If paternity is assured, the paternal blood type is usually determined to predict fetal risk of inheriting the antigen that the maternal antibody is directed against. For most blood group systems, serological testing of the father's blood type is sufficient to predict homozygosity or heterozygosity of the antigen. For instance, anti-K and anti-k antisera can detect K and k antigens, respectively, and provide accurate prediction of the risk that the fetus has inherited the blood group antigen. For RhD, serological testing alone cannot predict the number of RhD genes that the father carries because there is no antithetical allele for the RhD gene. Thus, in the case of maternal anti-D sensitization, paternal genotyping to detect copy number of the RhD gene is recommended. 16   Fetuses may bear a 50% risk of antigen inheritance when testing identifies paternal heterozygosity for the antigen in question.. Direct fetal genotyping can determine fetal blood group expression in these settings and provide accurate prediction of fetal risk for HDFN in sensitized mothers. Red cell genotyping can be accomplished using fetal amniocyte genetic testing (obtained via amniocentesis or chorionic villus sampling), or using fetal DNA obtained from maternal serum. 17   The latter methodology has found broad appeal due to its noninvasive approach. 18  

For pregnancies at risk of HDFN due to maternal alloimmunization and possible fetal RBC expression of the cognate antigen, prenatal care by maternal–fetal medicine physicians is recommended. A detailed maternal history is useful to determine previous pregnancy outcomes, particularly for past stillbirths or hydropic fetal losses, and potential etiology of the offending red cell antibody. In addition, fetal ultrasound to determine gestational age and absence of ascites is indicated. 19  

The red cell antibody titer, or strength, helps with further stratification, although the relatively subjective nature of these assays should always be kept in mind. 20 , 21   Traditionally, serial antibody titers are used to detect ongoing sensitization, with arbitrary thresholds of increasing antibody strength used to indicate ongoing and increasing immune stimulation, presumably due to the presence of fetal red cell antigen. If there was a previously affected pregnancy, trending of the titer will not be a reliable measure of increasing sensitization. In addition, transfusion laboratories establish critical antibody titers at which the antibody strength has reached a level that may lead to significant fetal anemia (titers of 1:16-32 are commonly used). 4   However, because the Kell blood group antigens are present on early red cell precursors, a maternal anti-K of relatively low titer, such as 8, may lead to severe hypoproliferative anemia. 22   Using other techniques for antibody strength determination, such as flow cytometry, may be more precise than antibody titers. 23  

For pregnancies that have reached 16-24 weeks, or when a critical antibody titer is reached (depending on maternal history of previously affected pregnancies), fetal anemia is monitored using cerebral MCA Doppler velocity measurements every 2 weeks for risk stratification ( Figure 1 ). 19 , 24   Correlative studies support that the use of the noninvasive MCA Doppler technique as a surrogate measurement for assessing fetal anemia. 19   Doppler readings that are >1.5 multiples of the mean (MoM) are very sensitive, with a 12% false-positive rate, thus trending is important. Weekly fetal monitoring, such as ultrasound and fetal heart rate monitoring, is also often performed).

Diagram of fetal middle cerebral artery Doppler velocimetry testing. Adapted from Moise 42   with permission.

When fetal anemia becomes moderate to severe as indicated by Doppler MoM measurements exceeding 1.5, invasive testing via cordocentesis is done to determine fetal hematocrit. If the fetus has not reached an acceptable gestational age for delivery, and the hematocrit level is <30%, intrauterine transfusion is usually indicated. Blood products for fetal transfusion should be ready at the start of the procedure for immediate use. Intrauterine transfusion (IUT) is performed by inserting a needle into the umbilical vein using ultrasound guidance and infusion of red cells at a predetermined hematocrit level. The selection of red cell products for intrauterine transfusion is typically Group O, Rh D-negative (or -positive, depending on maternal blood group antibody), leukocyte reduced, hemoglobin S-negative, CMV-safe (CMV seronegative or leukocyte reduced), irradiated, and antigen-negative for maternal red cell antibody/antibodies. Because authors have reported that there is a risk of additional maternal red cell antibody formation after IUT, some centers have adopted providing prospectively matched Rh C, c, E, e, and K-matched transfusions. 25   Despite this, there is evidence that women undergoing Rh- and K-matched IUTs still form additional alloantibodies [to Duffy (FY), Kidd (JK) and (MNS) S blood group antigens]. 26   Following one or more IUT procedures, the fetal circulation is comprised primarily of donor red cells, as fetal marrow production is suppressed and the remaining circulating red cells are destroyed. 27   The procedure of intrauterine transfusion carries a 1%-3% risk of fetal adverse events such as infection or rupture of membranes; procedure outcomes in the early second trimester are poor. 28-30  

Small patient series have explored using maternal treatment with plasma exchange and/or intravenous immunoglobulin (IVIG) to blunt the effect of the maternal antibody on the fetal red cells with some success. 31   The American Society for Apheresis considers plasma exchange in this setting a Category II (second line therapy), with a weak grade of evidence. 32   The ultimate decision for delivery is based on the treating physician's judgement, and it is standard to maintain pregnancy until the fetus has reached a safe gestational age. For severely affected fetuses, the risk of continued monitoring and intrauterine transfusion is balanced against this, and most suggest delivery at 37-38weeks, although earlier delivery may be warranted in severe HDFN. 24  

At birth, the connection to the maternal circulation is severed, and the risk of neonatal hyperbilirubinemia increases significantly because of the immature development of the metabolic pathway to break down bilirubin in the neonatal liver. Although most jaundice in newborns is benign, management of hyperbilirubinemia is critical in the neonatal period because of the risk for bilirubin-induced encephalopathy. 33   Affected infants may need phototherapy to oxidize unconjugated bilirubin to allow for urinary excretion. For patients with known HDFN, close observation of bilirubin levels and hemoglobin is warranted to determine whether neonatal exchange transfusion is needed to wash out bilirubin and maternal antibody, and/or if transfusions are indicated to support oxygen carrying capacity to the tissues. 8   Administration of IVIG to the newborn has been used to reduce the need for exchange transfusions and phototherapy, but it does not affect the need for top off transfusions, and a Cochrane review suggests that more study is needed to determine the best use of IVIG in this setting. 8   When levels of bilirubin reach critical levels, exchange transfusion is indicated ( Table 3 ). Blood product selection is similar to that of IUT, however, because infant whole blood is also being removed, the RBC unit is usually mixed with a plasma unit to create reconstituted whole blood. After a two-volume exchange transfusion, ∼90% of the red cells have been replaced and 50% of the bilirubin has been removed. After exchange transfusion, a platelet count should be performed to monitor for iatrogenic thrombocytopenia.

Guidelines for exchange transfusion in infants 35 or more weeks gestation

During birth hospitalization, exchange transfusion is recommended if the TSB rises to these levels despite intensive phototherapy. For readmitted infants, if the TSB level is above the exchange level, repeat TSB measurement every 2-3 hours and consider exchange if the TSB remains above the levels indicated after intensive phototherapy for 6 hours.

Adapted from the Clinical Guideline for Management of Hyperbilirubinemia. 33  

Hyporegenerative anemia can last for many weeks after birth ( Table 1 ). Infants must be carefully monitored for clinical signs of ongoing anemia, whichis most likely manifested by poor feeding, the most aerobic activity for neonates. They may also have increased sleep as anemia worsens. In ongoing anemia, the reticulocyte production from the fetal bone marrow may be decreased, and other cells lines, such as neutrophils can be affected. Weekly monitoring of reticulocytes and hematocrit will help to guide decision making about transfusion, and also provide reassurance when the marrow is recovering.

Prevention of HDFN can be divided into primary and secondary measures; there are no international standards, thus, nations differ on preventative measures including dosing and dosing schedules of RhIg and approach to transfusion. Primary prevention focuses on prevention of maternal alloimmunization in the first pregnancy. This is encompassed by the policy employed by some transfusion services, or blood banks, to provide red cell transfusions to females of childbearing potential that are more highly matched than standard transfusions to prevent transfusion-induced red cell sensitization. For instance, in some European countries, K-negative RBC units are provided to women younger than 45-50 years of age. Other nations provide additional matching for antigens, such as c and E. 34   In a retrospective review in Croatia, 48% of 214 pregnancies with maternal sensitization to E, K, or c had a history of transfusion, suggesting that matching for these antigens may be protective, however, the paternal antigen status was not reported. 35   A study in the Netherlands found that a proportion of maternal sensitization to non-RhD blood groups with clinically affected offspring was due to intrauterine transfusion itself. 26   Therefore, these measures may be effective in reducing the incidence of HDFN; however, further comparative studies are needed.

Secondary prevention of HDFN focuses on the RhD RBC antigen given that RhD immune globulin (RhIg) is available to prevent naïve RhD-negative immune systems from synthesizing anti-D antibody after exposure to small amounts of RhD antigen. The risk of an RhD-negative mother becoming allosensitized can be reduced to from 16% to <0.1% by the appropriate administration of RhIg. 13   At this time, there are no other pharmaceutical therapies that can prevent blood group sensitization for other blood group antigens. The transfusion service laboratory plays a critical role in guiding therapy with RhIg. For pregnant women who are RhD-negative, RhIg is typically administered at 2 time points over the course of the pregnancy. The first dose is provided at 28 weeks gestation, as recommended by the American College of Obstetricians and Gynecologists (ACOG) because the majority of allosensitization appears to occur after this time point, and the second after delivery of an RhD-positive infant. 36   The 28 week dose reduces the rate of allosensitization to RhD from 1.5% (antenatal administration only) to 0.1%. As noted above, any procedure or trauma that increases the rate of fetomaternal hemorrhage should elicit the administration of an additional RhIg dose. The antenatal RhIg dose is increased when the volume of fetomaternal hemorrhage is found to be ≥10 mL using the Kleihauer–Betke test. Although used for many years, the Kleihauer–Betke test has been found to be imprecise, and recent attention has focused on newer technologies, such as flow cytometry to provide more accurate quantification of the FMH volume 37  

As molecular testing advances throughout the field of medicine, so does the application of blood typing using molecular techniques. In certain patients, serological reagents do not accurately detect the RhD type. The most common genetic backgrounds that account for this serological typing problem are called weak D phenotypes. Recently, authors have encouraged the use of RhD genetic testing for patients with a weak D phenotype to provide accurate and actionable results for RhD blood typing and RhIg administration. 38 , 39   Further scientific study is needed to elucidate the clinical significance of different RhD genotypes in various ethnic backgrounds and the risk factors for RhIg failure. 40   Precise determination of fetal RhD typing has been widely accepted in Europe and improved the ability to guide RhIg therapy. 18  

In conclusion, HDFN is a multifaceted disease that has distinct technical considerations over several critical time periods of fetal and neonatal development. Advances in maternal–fetal medicine, such as the inventions of RhIg, IUT and noninvasive fetal genetic testing, have led to dramatic improvements in the outcomes of HDFN and prevention of maternal allosensitization. 41   Future advances in blood typing and noninvasive testing will continue to improve the care of mothers and their offspring affected by blood group incompatibility.

Meghan Delaney, Bloodworks NW, 921 Terry Ave, Seattle, WA 98104; Phone: 206-689-6500; e-mail: [email protected] .

Competing Interests

Conflict-of-interest disclosures: M.D. has consulted for Williams Kastner and has received honoraria from Grifols/Novartis and Bioarray/Immucor; and D.C.M. declares no competing financial interests.

Author notes

Off-label drug use: IVIG is included as a therapy for mothers with HDFN. This will be discussed in brief.

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Hemolytic Disease of the Newborn

Children's hospital of philadelphia, what is hemolytic disease of the newborn (hdn).

Hemolytic disease of the newborn is also called erythroblastosis fetalis. This condition occurs when there is an incompatibility between the blood types of the mother and baby.

"Hemolytic" means breaking down of red blood cells

"Erythroblastosis" refers to making of immature red blood cells

"Fetalis" refers to fetus

What causes hemolytic disease of the newborn (HDN)?

HDN most frequently occurs when an Rh negative mother has a baby with an Rh positive father. When the baby's Rh factor is positive, like the father's, problems can develop if the baby's red blood cells cross to the Rh negative mother. This usually happens at delivery when the placenta detaches. However, it may also happen anytime blood cells of the two circulations mix, such as during a miscarriage or abortion, with a fall, or during an invasive prenatal testing procedure (such as an amniocentesis or chorionic villus sampling).

The mother's immune system sees the baby's Rh positive red blood cells as "foreign." Just as when bacteria invade the body, the immune system responds by developing antibodies to fight and destroy these foreign cells. The mother's immune system then keeps the antibodies in case the foreign cells appear again, even in a future pregnancy. The mother is now "Rh sensitized."

In a first pregnancy, Rh sensitization is not likely. Usually, it only becomes a problem in a future pregnancy with another Rh positive baby. During that pregnancy, the mother's antibodies cross the placenta to fight the Rh positive cells in the baby's body. As the antibodies destroy the red blood cells, the baby can become sick. This is called erythroblastosis fetalis during pregnancy. In the newborn, the condition is called hemolytic disease of the newborn.

Who is affected by hemolytic disease of the newborn?

Babies affected by HDN are usually in a mother's second or higher pregnancy, after she has become sensitized with a first baby. HDN due to Rh incompatibility is about three times more likely in Caucasian babies than African-American babies.

Why is hemolytic disease of the newborn a concern?

When the mother's antibodies attack the red blood cells, they are broken down and destroyed (hemolysis). This makes the baby anemic. Anemia is dangerous because it limits the ability of the blood to carry oxygen to the baby's organs and tissues. As a result:

The baby's body responds to the hemolysis by trying to make more red blood cells very quickly in the bone marrow and the liver and spleen. This causes these organs to get bigger. The new red blood cells, called erythroblasts, are often immature and are not able to do the work of mature red blood cells.

As the red blood cells break down, a substance called bilirubin is formed. Babies are not easily able to get rid of the bilirubin and it can build up in the blood and other tissues and fluids of the baby's body. This is called hyperbilirubinemia. Because bilirubin has a pigment or coloring, it causes a yellowing of the baby's skin and tissues. This is called jaundice.

Complications of hemolytic disease of the newborn can range from mild to severe. The following are some of the problems that can result:

During pregnancy:

Mild anemia, hyperbilirubinemia, and jaundice. The placenta helps rid some of the bilirubin, but not all.

Severe anemia with enlargement of the liver and spleen. When these organs and the bone marrow cannot compensate for the fast destruction of red blood cells, severe anemia results and other organs are affected.

Hydrops fetalis. This occurs as the baby's organs are unable to handle the anemia. The heart begins to fail and large amounts of fluid build up in the baby's tissues and organs. A fetus with hydrops is at great risk of being stillborn.

After birth:

Severe hyperbilirubinemia and jaundice. The baby's liver is unable to handle the large amount of bilirubin that results from red blood cell breakdown. The baby's liver is enlarged and anemia continues.

Kernicterus. Kernicterus is the most severe form of hyperbilirubinemia and results from the buildup of bilirubin in the brain. This can cause seizures, brain damage, deafness, and death.

What are the symptoms of hemolytic disease of the newborn?

The following are the most common symptoms of hemolytic disease of the newborn. However, each baby may experience symptoms differently. During pregnancy symptoms may include:

With amniocentesis, the amniotic fluid may have a yellow coloring and contain bilirubin.

Ultrasound of the fetus shows enlarged liver, spleen, or heart and fluid buildup in the fetus's abdomen, around the lungs, or in the scalp.

After birth, symptoms may include:

A pale coloring may be evident, due to anemia.

Jaundice, or yellow coloring of amniotic fluid, umbilical cord, skin, and eyes may be present. The baby may not look yellow immediately after birth, but jaundice can develop quickly, usually within 24 to 36 hours.

The newborn may have an enlarged liver and spleen.

Babies with hydrops fetalis have severe edema (swelling) of the entire body and are extremely pale. They often have difficulty breathing.

How is hemolytic disease of the newborn diagnosed?

Because anemia, hyperbilirubinemia, and hydrops fetalis can occur with other diseases and conditions, the accurate diagnosis of HDN depends on determining if there is a blood group or blood type incompatibility. Sometimes, the diagnosis can be made during pregnancy based on information from the following tests:

Testing for the presence of Rh positive antibodies in the mother's blood

Ultrasound - to detect organ enlargement or fluid buildup in the fetus. Ultrasound is a diagnostic imaging technique which uses high-frequency sound waves and a computer to create images of blood vessels, tissues, and organs. Ultrasound is used to view internal organs as they function, and to assess blood flow through various vessels.

Amniocentesis - to measure the amount of bilirubin in the amniotic fluid. Amniocentesis is a test performed to determine chromosomal and genetic disorders and certain birth defects. The test involves inserting a needle through the abdominal and uterine wall into the amniotic sac to retrieve a sample of amniotic fluid.

Sampling of some of the blood from the fetal umbilical cord during pregnancy to check for antibodies, bilirubin, and anemia in the fetus.

Once a baby is born, diagnostic tests for HDN may include the following:

Testing of the baby's umbilical cord blood for blood group, Rh factor, red blood cell count, and antibodies

Testing of the baby's blood for bilirubin levels

Treatment for hemolytic disease of the newborn

Once HDN is diagnosed, treatment may be needed. Specific treatment for hemolytic disease of the newborn will be determined by your baby's doctor based on:

Your baby's gestational age, overall health, and medical history

Extent of the disease

Your baby's tolerance for specific medications, procedures, or therapies

Expectations for the course of the disease

Your opinion or preference

During pregnancy, treatment for HDN may include:

Intrauterine blood transfusion of red blood cells into the baby's circulation. This is done by placing a needle through the mother's uterus and into the abdominal cavity of the fetus or directly into the vein in the umbilical cord. It may be necessary to give a sedative medication to keep the baby from moving. Intrauterine transfusions may need to be repeated.

Early delivery if the fetus develops complications. If the fetus has mature lungs, labor and delivery may be induced to prevent worsening of HDN.

After birth, treatment may include:

Blood transfusions (for severe anemia)

Intravenous fluids (for low blood pressure)

Help for respiratory distress using oxygen, surfactant,  or a mechanical breathing machine

Exchange transfusion to replace the baby's damaged blood with fresh blood. The exchange transfusion helps increase the red blood cell count and lower the levels of bilirubin. An exchange transfusion is done by alternating giving and withdrawing blood in small amounts through a vein or artery. Exchange transfusions may need to be repeated if the bilirubin levels remain high.

Intravenous immunoglobin(IVIG). IVIG is a solution made from blood plasma that contains antibodies to help the baby's immune system. IVIG may help reduce the breakdown of red blood cells and lower bilirubin levels.  

Prevention of hemolytic disease of the newborn

Fortunately, HDN is a very preventable disease. Because of the advances in prenatal care, nearly all women with Rh negative blood are identified in early pregnancy by blood testing. If a mother is Rh negative and has not been sensitized, she is usually given a drug called Rh immunoglobulin (RhIg), also known as RhoGAM. This is a specially developed blood product that can prevent an Rh negative mother's antibodies from being able to react to Rh positive cells. Many women are given RhoGAM around the 28th week of pregnancy. After the baby is born, a woman should receive a second dose of the drug within 72 hours, if her baby is Rh positive. If her baby is Rh negative, she does not need another dose.

• Case report
• Open access
• Published: 20 February 2012

Hemolytic disease of the fetus and newborn caused by anti-D and anti-S alloantibodies: a case report

• Rabeya Yousuf 1 ,
• Suria Abdul Aziz 1 ,
• Nurasyikin Yusof 1 &
• Chooi-Fun Leong 1  

Journal of Medical Case Reports volume  6 , Article number:  71 ( 2012 ) Cite this article

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Introduction

Hemolytic disease of the fetus and newborn is most commonly caused by anti-D alloantibody. It is usually seen in Rhesus D (RhD)-negative mothers that have been previously sensitized. We report here a case of hemolytic disease of the fetus and newborn in a newborn baby caused by anti-D and anti-S alloantibodies, born to a mother who was RhD negative, but with no previous serological evidence of RhD alloimmunization.

Case presentation

A one-day-old Chinese baby boy was born to a mother who was group A RhD negative. The baby was jaundiced with hyperbilirubinemia, but with no evidence of infection. His blood group was group A RhD positive, his direct Coombs' test result was positive and red cell elution studies demonstrated the presence of anti-D and anti-S alloantibodies. Investigations performed on the maternal blood during the 22 weeks of gestation showed the presence of anti-S antibodies only. Repeat investigations performed post-natally showed the presence of similar antibodies as in the newborn and an anti-D titer of 1:32 (0.25 IU/mL), which was significant. A diagnosis of hemolytic disease of the fetus and newborn secondary to anti-D and anti-S was made. The baby was treated with phototherapy and close monitoring. He was discharged well after five days of phototherapy.

Conclusions

This case illustrates the possibility of an anamnestic response of allo-anti-D from previous sensitization in a RhD-negative mother, or the development of anti-D in mid-trimester. Thus, it highlights the importance of thorough antenatal ABO, RhD blood grouping and antibody screening, and if necessary, antibody identification and regular monitoring of antibody screening and antibody levels for prevention or early detection of hemolytic disease of the fetus and newborn, especially in cases of mothers with clinically significant red cell alloantibody.

Peer Review reports

Hemolytic disease of the fetus and newborn (HDFN) is characterized by the presence of IgG antibodies in the maternal circulation, directed against a paternally derived antigen present in the fetal/neonatal red cells that cause hemolysis in the fetus by crossing the placenta and sensitizing red cells for destruction by the macrophages in the fetal spleen [ 1 ]. It was first described in 1609 by a French midwife [ 2 ] but established in 1939 by Levine and Stetson. They reported a transfusion reaction from transfusing the husband's blood to a postpartum woman who had been immunized through a feto-maternal hemorrhage [ 3 ]. The serological tests for the diagnosis of HDFN includes a positive direct Coombs' test (DCT) on the baby's red blood cells and the presence of an IgG red cell alloantibody in both cord blood eluate and maternal sera. The presence of the corresponding antigen on cord cells confirms the diagnosis of HDFN [ 4 , 5 ]. The most severe HDFN is caused by IgG antibodies directed against D, c or K antigens on the fetal red cells, but any IgG antibodies can cause HDFN [ 6 ]. Anti-S has been documented as a rare cause of HDFN [ 7 ].

In this study, we report a case of HDFN caused by anti-D and anti-S in a para 3+1 mother who had no anti-D antibodies detected during the first trimester of pregnancy. The presence of allo-anti-D in the newborn and the mother herself postpartum may suggest an anamnestic response from previous sensitization or the development of anti-D during early trimesters of pregnancy. It also highlights the importance of regular monitoring of antibody screening in pregnant women, especially Rhesus D (RhD)-negative mothers, in view of the high immunogenicity of the RhD antigen.

A full-term, Chinese baby boy was born to a 30-year-old woman at 38 weeks of gestation. The baby weighed 2.8 kg with an Apgar score of 9/10. The baby was noted to have mild jaundice with normal vital signs on day one of life; there was no evidence to suggest other causes of neonatal jaundice such as intrauterine infections and his glucose-6-phosphate dehydrogenase screen was normal. Laboratory investigations showed that his total bilirubin was 198 μmol/L and hemoglobin was 19 g/dL. The baby's blood group was A RhD positive with a red cell phenotype of ccDEe (R2r) and SS. The result of a DCT was positive and red cell elution studies of the baby's blood identified the presence of anti-D and anti-S antibodies.

The mother was para 3+1. Her first pregnancy was aborted five years ago and unfortunately no investigation was performed to find out the cause of abortion. Subsequent pregnancies were uneventful with no history of HDFN in the last three years. She denied any previous history of blood transfusion. Her transfusion record at our center showed that the mother developed anti-S antibodies during her second pregnancy three years ago. An antenatal antibody screening test performed at 22 weeks identified only allo-anti-S; no anti-D was detected. She was given RhD Ig prophylaxis at 28 weeks of pregnancy. Her other laboratory investigation results showed that she was grouped as A RhD negative with red cell phenotype ccdee (rr), and homozygous ss. At postpartum, the result of her DCT was negative, but the antibody screening test performed using the indirect Coombs' test method and antibody investigations showed the presence of anti-D and anti-S, and the anti-D titer was 1:32 (0.25 IU/mL).

In view of the presence of allo-anti-D and allo-anti-S in the postpartum maternal blood, supported by the presence of similar alloantibodies in the baby's red cell eluates and clinical presentation of hemolytic anemia, a diagnosis of hemolytic disease of the fetus and newborn secondary to anti-D and anti-S was made. The baby was immediately started on a course of conventional phototherapy with a single tungsten halogen bulb. His serum bilirubin levels subsequently reduced to normal levels over a few days. On the sixth day of life, the baby was discharged well with no complications.

This case illustrates an uncommon case of HDFN caused by anti-D and anti-S antibodies, which were identified from the red cell eluate of the baby as well as the mother's serum post-natally. In this case, there was no anti-D detected at 22 weeks of gestation and there was no subsequent follow-up at our center. However, at postpartum, when the newborn developed jaundice an investigation for HDFN demonstrated that there were both anti-D and anti-S. The possible explanation for the anti-D at postpartum could be due to (a) RhD Ig prophylaxis given at the early third trimester of pregnancy. A previous case report by Hensley et al. [ 8 ] showed that the maternal antibody screen becomes normal at 37 weeks of pregnancy in a mother who was given an RhD Ig prophylaxis at 28 weeks of pregnancy. The maternal serum sample was taken 40 minutes after RhD Ig immunization and showed an anti-D titer of 1:8, which subsequently peaked at a titer of 1:32 at 24 hours and remained at that level for about two weeks and then leveled off at 1:16 from week three through to week nine. At term, about 37 weeks of gestation, the maternal antibody screens reverted to normal [ 8 ]. Besides that, it is thought that the administration of RhD Ig during pregnancy can cause a positive antibody screening in the mother but the anti-D titer rarely reaches above 1:4 [ 9 ]. In our case study, the mother claimed that she was only given RhD Ig at 28 weeks of gestation and her anti-D titer was 1:32 (0.25 IU/mL). The high anti-D titer of 1:32 in our case study is most probably due to RhD alloimmunization from exposure of the mother to RhD positive fetal red blood cells later in gestation and unlikely to be due to the administration of RhD Ig at 28 weeks.

Another possible explanation could be (b) an anamnestic response to anti-D. The mother could have had previous exposure to the RhD antigen during her previous abortion or pregnancies, and these anti-D antibodies were not initially detectable in her plasma but subsequent exposure to the RhD antigen from this pregnancy at a later point provoked a rapid and robust production of anti-D antibodies. The titer detected was also significant, as it is described in the literature that anti-D titers of ≥1:32 are significant and can lead to HDFN [ 3 , 9 ]. Unfortunately, we were unable to differentiate between the two concentrations without the regular monitoring of antibody screening and identification and quantification of the antibody titer in our patient.

Anti-S antibody is an IgG antibody developed following red cell alloimmunization. It is reactive at 37°C and best detected by the indirect antiglobulin test. A literature search revealed that anti-S is a rare cause of HDFN and usually presents as a mild form of jaundice [ 7 ]. However, there are a few reports of severe and fatal HDFN due to this antibody. The first case of severe HDFN due to anti-S was described as early as 1952 where a baby died secondary to kernicterus at 60 hours of life [ 10 ]. Griffith [ 11 ] and Mayne et al. [ 12 ] also identified two other cases of severe HDFN due to anti-S. Fortunately, in our patient, despite the presence of anti-D and anti-S on the baby's red cells, the severity of HDFN was relatively mild and the baby's condition improved with phototherapy.

In this report of an uncommon case of HDFN due to anti-D and anti-S antibodies, the detection of anti-D in postpartum serum could be explained by the anamnestic effect of previous alloimmunization or the sensitization after 22 weeks of gestation in the mother's current pregnancy. This case report highlights the importance of regular antenatal follow-up and monitoring of red cell alloantibody development and antibody titers, especially in a mother who is RhD negative. This is because the red blood cell alloantibody may lead to HDFN of variable severity, and early detection in utero may allow early intervention and thus minimize morbidity at birth.

Written informed consent was obtained from the patient's legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

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Rabeya Yousuf, Suria Abdul Aziz, Nurasyikin Yusof & Chooi-Fun Leong

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RY obtained the case history and consent from our patient's mother. SAA and NY analyzed and interpreted our patient's laboratory investigation results and assisted with the literature review. RY and LCF played a major role in the literature review and writing the manuscript. LCF edited the manuscript. All authors read and approved the final manuscript.

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Yousuf, R., Abdul Aziz, S., Yusof, N. et al. Hemolytic disease of the fetus and newborn caused by anti-D and anti-S alloantibodies: a case report. J Med Case Reports 6 , 71 (2012). https://doi.org/10.1186/1752-1947-6-71

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Received : 27 October 2011

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DOI : https://doi.org/10.1186/1752-1947-6-71

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Health Encyclopedia

Hemolytic disease of the newborn (hdn), what is hemolytic disease of the newborn.

Hemolytic disease of the newborn (HDN) is a blood problem in newborn babies. It occurs when your baby's red blood cells break down at a fast rate. It’s also called erythroblastosis fetalis. 

Hemolytic means breaking down of red blood cells.

Erythroblastosis means making immature red blood cells.

Fetalis means fetus.

What causes HDN in a newborn?

All people have a blood type (A, B, AB, or O). Everyone also has an Rh factor (positive or negative). There can be a problem if a mother and baby have a different blood type and Rh factor.

HDN happens most often when an Rh negative mother has a baby with an Rh positive father. If the baby's Rh factor is positive, like their father's, this can be an issue if the baby's red blood cells cross to the Rh negative mother.

This often happens at birth when the placenta breaks away. But it may also happen any time the mother’s and baby's blood cells mix. This can occur during a miscarriage or fall. It may also happen during a prenatal test. These can include amniocentesis or chorionic villus sampling. These tests use a needle to take a sample of tissue. They may cause bleeding.

The Rh negative mother’s immune system sees the baby's Rh positive red blood cells as foreign. Your immune system responds by making antibodies to fight and destroy these foreign cells. Your immune system stores these antibodies in case these foreign cells come back again. This can happen in a future pregnancy. You are now Rh sensitized.

Rh sensitization normally isn’t a problem with a first pregnancy. Most problems occur in future pregnancies with another Rh positive baby. During that pregnancy, the mother's antibodies cross the placenta to fight the Rh positive cells in the baby's body. As the antibodies destroy the cells, the baby gets sick. This is called erythroblastosis fetalis during pregnancy. Once the baby is born, it’s called HDN.

Which children are at risk for HDN?

The following can raise your risk for having a baby with HDN:

You’re Rh negative and have an Rh positive baby but haven’t received treatment.

You’re Rh negative and have been sensitized. This can happen in a past pregnancy with an Rh positive baby. Or it can happen because of an injury or test in this pregnancy with an Rh positive baby. 

HDN is about 3 times more common in white babies than in African-American babies.

What are the symptoms of HDN in a newborn?

Symptoms can occur a bit differently in each pregnancy and child.

During pregnancy, you won't notice any symptoms. But your healthcare provider may see the following during a prenatal test:

A yellow coloring of amniotic fluid. This color may be because of bilirubin. This is a substance that forms as blood cells break down.

Your baby may have a big liver, spleen, or heart. There may also be extra fluid in their stomach, lungs, or scalp. These are signs of hydrops fetalis. This condition causes severe swelling (edema).

After birth, symptoms in your baby may include:

Pale-looking skin. This is from having too few red blood cells (anemia).

Yellow coloring of your baby’s umbilical cord, skin, and the whites of their eyes (jaundice). Your baby may not look yellow right after birth. But jaundice can come on quickly. It often starts in 24 to 36 hours.  

Your newborn may have a big liver and spleen.

A newborn with hydrops fetalis may have severe swelling of their entire body. They may also be very pale and have trouble breathing.

How is HDN diagnosed in a newborn?

HDN can cause symptoms similar to those caused by other conditions. To make a diagnosis, your child’s healthcare provider will look for blood types that cannot work together. Sometimes this diagnosis is made during pregnancy. It will be based on results from the following tests:

Blood test. Testing is done to look for Rh positive antibodies in your blood.

Ultrasound. This test can show enlarged organs or fluid buildup in your baby.

Amniocentesis. This test is done to check the amount of bilirubin in the amniotic fluid. In this test, a needle is put into your abdominal and uterine wall. It goes through to the amniotic sac. The needle takes a sample of amniotic fluid.

Percutaneous umbilical cord blood sampling. This test is also called fetal blood sampling. In this test, a blood sample is taken from your baby’s umbilical cord. Your child’s healthcare provider will check this blood for antibodies, bilirubin, and anemia. This is done to check if your baby needs an intrauterine blood transfusion.

The following tests are used to diagnose HDN after your baby is born:

Testing of your baby's umbilical cord. This can show your baby’s blood group, Rh factor, red blood cell count, and antibodies.

Testing of the baby's blood for bilirubin levels.

How is HDN treated in a newborn?

During pregnancy, treatment for HDN may include the following.

A healthcare provider will check your baby’s blood flow with an ultrasound.

Intrauterine blood transfusion

This test puts red blood cells into your baby's circulation. In this test, a needle is placed through your uterus. It goes into your baby’s abdominal cavity to a vein in the umbilical cord. Your baby may need sedative medicine to keep them from moving. You may need to have more than 1 transfusion.

Early delivery

If your baby gets certain complications, they may need to be born early. Your healthcare provider may induce labor once your baby has mature lungs. This can keep HDN from getting worse.  

After birth, treatment may include the following.

Blood transfusions

This may be done if your baby has severe anemia.

Intravenous fluids

This may be done if your baby has low blood pressure.

Phototherapy

In this test, your baby is put under a special light. This helps your baby get rid of extra bilirubin.

Help with breathing

Your baby may need oxygen, a substance in the lungs that helps keep the tiny air sacs open (surfactant), or a mechanical breathing machine (ventilator) to breathe better.

Exchange transfusion

This test removes your baby’s blood that has a high bilirubin level. It replaces it with fresh blood that has a normal bilirubin level. This raises your baby’s red blood cell count. It also lowers their bilirubin level. In this test, your baby will alternate giving and getting small amounts of blood. This will be done through a vein or artery. Your baby may need to have this procedure again if their bilirubin levels stay high.

Intravenous immunoglobulin (IVIG)

IVIG is a solution made from blood plasma. It contains antibodies to help the baby's immune system. IVIG reduces your baby’s breakdown of red blood cells. It may also lower their bilirubin levels.  

What are possible complications of HDN in a newborn?

When your antibodies attack your baby’s red blood cells, they are broken down and destroyed (hemolysis).

When your baby’s red blood cells break down, bilirubin is formed. It’s hard for babies to get rid of bilirubin. It can build up in their blood, tissues, and fluids. This is called hyperbilirubinemia. Bilirubin makes a baby’s skin, eyes, and other tissues to turn yellow. This is called jaundice.

When red blood cells breakdown, this makes your baby anemic. Anemia is dangerous. In anemia, your baby’s blood makes more red blood cells very quickly. This happens in the bone marrow, liver, and spleen. This causes these organs to get bigger. The new red blood cells are often immature and can’t do the work of mature red blood cells.

Complications of HDN can be mild or severe.

During pregnancy, your baby may have the following:

Mild anemia, hyperbilirubinemia, and jaundice. The placenta gets rid of some bilirubin. But it can’t remove all of it.

Severe anemia. This can cause your baby’s liver and spleen to get too big. This can also affect other organs.

Hydrops fetalis. This happens when your baby's organs aren’t able to handle the anemia. Your baby’s heart will start to fail. This will cause large amounts of fluid buildup in your baby's tissues and organs. Babies with this condition are at risk for being stillborn.

After birth, your baby may have the following:

Severe hyperbilirubinemia and jaundice. Your baby’s liver can’t handle the large amount of bilirubin. This causes your baby’s liver to grow too big. They will still have anemia.

Kernicterus. This is the most severe form of hyperbilirubinemia. It’s because of the buildup of bilirubin in your baby’s brain. This can cause seizures, brain damage, and deafness. It can even cause death.

What can I do to prevent hemolytic disease of the newborn?

HDN can be prevented. Almost all women will have a blood test to learn their blood type early in pregnancy.

If you’re Rh negative and have not been sensitized, you’ll get a medicine called Rh immunoglobulin (RhoGAM). This medicine can stop your antibodies from reacting to your baby’s Rh positive cells. Many women get RhoGAM around week 28 of pregnancy.

If your baby is Rh positive, you’ll get a second dose of medicine within 72 hours of giving birth. If your baby is Rh negative, you won’t need a second dose

Key points about hemolytic disease of the newborn

HDN occurs when your baby's red blood cells break down at a fast rate.

HDN happens when an Rh negative mother has a baby with an Rh positive father.

If the Rh negative mother has been sensitized to Rh positive blood, her immune system will make antibodies to attack her baby.

When the antibodies enter the baby's blood, they will attack the red blood cells. This causes them to break down. This can cause problems.

This condition can be prevented. Women who are Rh negative and haven’t been sensitized can receive medicine. This medicine can stop your antibodies from reacting to your baby’s Rh positive cells.

Tips to help you get the most from a visit to your child’s healthcare provider:

Know the reason for the visit and what you want to happen.

Before your visit, write down questions you want answered.

At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you for your child.

Know why a new medicine or treatment is prescribed and how it will help your child. Also know what the side effects are.

Ask if your child’s condition can be treated in other ways.

Know why a test or procedure is recommended and what the results could mean.

Know what to expect if your child does not take the medicine or have the test or procedure.

If your child has a follow-up appointment, write down the date, time, and purpose for that visit.

Know how you can contact your child’s provider after office hours. This is important if your child becomes ill and you have questions or need advice.

Medical Reviewers:

• Donna Freeborn PhD CNM FNP
• Heather M Trevino BSN RNC
• Irina Burd MD PhD
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Hemolytic Disease of the Fetus and Newborn

(rh incompatibility; erythroblastosis fetalis or neonatorum).

, MD, Main Line Health System

Rh incompatibility occurs when a pregnant woman has Rh-negative blood and the fetus has Rh-positive blood.

Rh incompatibility can result in destruction of the fetus’s red blood cells, sometimes causing anemia that can be severe.

The fetus of a women with Rh-negative blood and a man with Rh-positive blood is checked periodically for evidence of anemia.

If anemia is suspected, the fetus is given blood transfusions.

To prevent problems in the fetus, doctors give injections of Rh antibodies to women with Rh-negative blood at about 28 weeks of pregnancy, after any episode of significant bleeding, after delivery, and after certain procedures.

Pregnancy complications, such as Rh incompatibility, are problems that occur only during pregnancy. They may affect the woman, the fetus, or both and may occur at different times during the pregnancy. However, most pregnancy complications can be effectively treated.

The fetus of a woman with Rh-negative blood may have Rh-positive blood if the father has Rh-positive blood. The percentage of people who have Rh-negative blood is small and varies by ethnicity:

White people in North America and Europe: About 15%

African American people: About 8%

People of Chinese descent: About 0.3%

People of Indian descent: About 5%

Did You Know...

In women with Rh-negative blood, sensitization can occur at any time during pregnancy. However, the most likely time is at delivery. In the pregnancy when sensitization first occurs, the fetus or newborn is not likely to be affected. Once women are sensitized, problems are more likely with each subsequent pregnancy if the fetus’s blood is Rh-positive. In each pregnancy after sensitization, women produce Rh antibodies earlier and in larger amounts.

If Rh antibodies cross the placenta to the fetus, they may destroy some of the fetus’s red blood cells. If red blood cells are destroyed faster than the fetus can produce new ones, the fetus can develop anemia. Such destruction is called hemolytic disease of the fetus Hemolytic Disease of the Newborn Hemolytic disease of the newborn is a condition in which red blood cells are broken down or destroyed by the mother's antibodies. Hemolysis is the breakdown of red blood cells. This disorder... read more (erythroblastosis fetalis) or of the newborn (erythroblastosis neonatorum).

Usually, Rh incompatibility causes no symptoms in pregnant women.

Occasionally, other molecules on the woman's red blood cells are incompatible with those of the fetus. Such incompatibility can cause problems similar to those of Rh incompatibility.

Diagnosis of Rh Incompatibility

Blood tests

If the woman's blood contains Rh antibodies, Doppler ultrasonography

At the first visit to a doctor during a pregnancy, all women are screened to determine what their blood type is, whether they have Rh-positive or Rh-negative blood, and whether they have Rh antibodies or other antibodies to red blood cells.

Doctors usually assess the risk of women with Rh-negative blood becoming sensitized to Rh factor and producing Rh antibodies as follows:

If the father is known and is available for testing, his blood type is determined.

If the father is unavailable for testing or if he was tested and he has Rh-positive blood, a blood test called cell-free fetal nucleic acid (DNA) testing can be done to determine whether the fetus has Rh-positive blood. For this test, doctors test small fragments of the fetus's DNA, which are present in the pregnant woman's blood in tiny amounts (usually after 10 to 11 weeks).

If the father has Rh-negative blood, no further testing is needed.

Prevention of Rh Incompatibility

As a precaution, women who have Rh-negative blood are given an injection of Rh antibodies at each of the following times:

At 28 weeks of pregnancy

Within 72 hours after delivery of a baby who has Rh-positive blood, even after a miscarriage or an abortion

After any episode of vaginal bleeding during pregnancy

After amniocentesis Amniocentesis Prenatal testing for genetic disorders and birth defects involves testing a pregnant woman or fetus before birth (prenatally) to determine whether the fetus has certain abnormalities, including... read more or chorionic villus sampling Chorionic Villus Sampling Prenatal testing for genetic disorders and birth defects involves testing a pregnant woman or fetus before birth (prenatally) to determine whether the fetus has certain abnormalities, including... read more

Sometimes, when large amounts of the fetus's blood enters the woman's bloodstream, additional injections are needed.

The antibodies given are called Rho(D) immune globulin. This treatment works by making the woman's immune system less able to recognize the Rh factor on red blood cells from the baby, which may have entered the woman’s bloodstream. Thus, the woman's immune system does not make antibodies to the Rh factor. Such treatment reduces the risk that the fetus's red blood cells will be destroyed in subsequent pregnancies from about 12 to 13% (without treatment) to about 0.1%.

Treatment of Rh Incompatibility

For anemia in the fetus, blood transfusions

Sometimes early delivery

If the fetus has Rh-negative blood or if results of tests continue to indicate that the fetus does not have anemia, the pregnancy can continue to term without any treatment.

If anemia is diagnosed in the fetus, the fetus can be given a blood transfusion before birth by a specialist at a center that specializes in high-risk pregnancies. Most often, the transfusion is given through a needle inserted into a vein in the umbilical cord. Usually, additional transfusions are given until 32 to 35 weeks of pregnancy. Exact timing of the transfusions depends on how severe the anemia is and how old the fetus is. Timing of delivery is based on the individual woman's situation.

Before the first transfusion, women are often given corticosteroids if the pregnancy has lasted 23 or 24 weeks or longer. Corticosteroids help the fetus's lungs mature and help prevent the common complications that can affect a preterm newborn Preterm (Premature) Newborns A preterm newborn is a baby delivered before 37 weeks of gestation. Depending on when they are born, preterm newborns may have underdeveloped organs that are not be ready to function outside... read more .

The baby may need additional transfusions after birth. Sometimes no transfusions are needed until after birth.

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• Open access
• Published: 07 January 2023

Hemolytic disease of the fetus and newborn: systematic literature review of the antenatal landscape

• Derek P. de Winter 1 , 2 ,
• Allysen Kaminski 3 , 4 ,
• May Lee Tjoa 5 &
• Dick Oepkes 6  

BMC Pregnancy and Childbirth volume  23 , Article number:  12 ( 2023 ) Cite this article

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Prevention of pregnancy-related alloimmunization and the management of hemolytic disease of the fetus and newborn (HDFN) has significantly improved over the past decades. Considering improvements in HDFN care, the objectives of this systematic literature review were to assess the prenatal treatment landscape and outcomes of Rh(D)- and K-mediated HDFN in mothers and fetuses, to identify the burden of disease, to identify evidence gaps in the literature, and to provide recommendations for future research.

We performed a systematic search on MEDLINE, EMBASE and clinicaltrials.gov. Observational studies, trials, modelling studies, systematic reviews of cohort studies, and case reports and series of women and/or their fetus with HDFN caused by Rhesus (Rh)D or Kell alloimmunization. Extracted data included prevalence; treatment patterns; clinical outcomes; treatment efficacy; and mortality.

We identified 2,541 articles. After excluding 2,482 articles and adding 1 article from screening systematic reviews, 60 articles were selected. Most abstracted data were from case reports and case series. Prevalence was 0.047% and 0.006% for Rh(D)- and K-mediated HDFN, respectively. Most commonly reported antenatal treatment was intrauterine transfusion (IUT; median frequency [interquartile range]: 13.0% [7.2–66.0]). Average gestational age at first IUT ranged between 25 and 27 weeks. weeks. This timing is early and carries risks, which were observed in outcomes associated with IUTs. The rate of hydrops fetalis among pregnancies with Rh(D)-mediated HDFN treated with IUT was 14.8% (range, 0–50%) and 39.2% in K-mediated HDFN. Overall mean ± SD fetal mortality rate that was found to be 19.8%±29.4% across 19 studies. Mean gestational age at birth ranged between 34 and 36 weeks.

These findings corroborate the rareness of HDFN and frequently needed intrauterine transfusion with inherent risks, and most births occur at a late preterm gestational age. We identified several evidence gaps providing opportunities for future studies.

Peer Review reports

Despite advances in the prevention of pregnancy-related red blood cell immunization and management and treatment of pregnancies affected by hemolytic disease of the fetus and newborn (HDFN) over recent decades, the disease still poses a significant risk in affected pregnancies [ 1 , 2 ]. HDFN is caused by maternal alloimmunization through exposure to incompatible red blood cell antigens of the fetus or through incompatible blood transfusion [ 1 , 3 ]. The then-formed immunoglobulin G (IgG) antibodies are actively transported across the placenta and can cause fetal hemolysis and anemia. When untreated, progressive fetal anemia results in hydrops fetalis and ultimately fetal demise. If the fetus survives, persistent hemolysis causes neonatal anemia and hyperbilirubinemia, which—when untreated—ultimately leads to a severe cerebral condition (“kernicterus”).

No cure exists for HDFN. Hence, interventions have focused on its prevention and minimizing adverse effects of associated complications [ 1 , 4 ]. Through transfusing women within the reproductive ages with Kell-negative donor blood, if possible, and through the introduction of Rhesus (Rh) immunoglobulin prophylaxis, the occurrence of red blood cell alloimmunization and the prevalence of Rh(D)- and K-mediated HDFN has decreased [ 1 , 4 , 5 , 6 ]; however, the gap between anti-Rh(D) supply and demand is large in low-income countries and is below the optimal threshold in high-income countries [ 7 ]. Additionally, the disease still poses a significant risk for mortality and morbidity in developing countries, whereas it is considered treatable with good outcomes in developed countries. Serological monitoring, ultrasonography, and Doppler imaging decreased the need for risky and invasive diagnostic procedures [ 3 , 8 , 9 , 10 , 11 , 12 ]. Antenatal treatment, however, still relies predominantly on (often serial) intrauterine transfusion (IUT)—an invasive procedure that carries maternal and fetal risks [ 13 , 14 ].

Considering improvements in HDFN care, the objectives of this systematic literature review were to assess the prenatal treatment landscape and outcomes of Rh(D)- and K-mediated HDFN in mothers and fetuses to identify the burden of disease, to identify evidence gaps in the literature, and to provide recommendations for future research. Secondarily, we aim to determine the humanistic and economic burden of HDFN.

Search strategy

We conducted a systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [ 15 ] and MOOSE Reporting Guidelines for Meta-Analysis of Observational Studies [ 16 ] to address prespecified research questions (Table S 2 ). To assess the treatment landscape, articles published between January 1, 2005, and March 10, 2021 were searched (Additional file 2 : Appendix S1) in the MEDLINE and EMBASE databases and ClinicalTrials.gov using ProQuest (Fig.  1 ). The search strategy included descriptions of the disease, possible interventions and clinical outcomes. No limitations were set on studies reporting on cases managed before January 1, 2005. Searches for clinical outcomes were performed for journal articles and conference abstracts indexed in EMBASE. Duplicates were removed automatically. We also manually searched reference lists of pertinent systematic literature reviews of cohort studies and our personal libraries for potentially relevant articles.

Flowchart of the Article Selection Process. SLR, systematic literature review.  * From authors’ personal library.  † From eligible SLRs of cohort studies 

Study selection

Two independent reviewers (D.P.D.W. and A.K.) (Table S 3 ) [ 17 ] reviewed the titles/abstracts in Rayyan ( https://rayyan.ai/ ) and then full texts in Microsoft Excel. Citations were independently evaluated to determine whether or not studies fulfilled inclusion and exclusion criteria. The project director (D.O.) and the project team adjudicated decisions. Randomized or nonrandomized trials; retrospective or prospective observational studies, including cohort, case-control, or cross-sectional studies; modelling studies; systematic reviews of cohort studies (to identify primary studies only); and case reports and case series of women and/or their fetuses, infants, or children experiencing or having experienced Rh(D)- and/or K-mediated HDFN were included. Studies or patient groups within studies where HDFN was caused by alloimmunization to antigens other than Rh(D) only and/or K only, such as c, e, E, Duffy (Fy), Kidd (Jk), MNS (S), or Gerbich, were excluded as the risk of prenatal disease is regarded as relatively low. Non–English-language articles were excluded, as were notes, editorials, and commentaries; nonsystematic reviews; reports of populations, interventions, outcomes, or study designs not of interest; publication types not of interest; indexed conference abstracts; and reports of animal or preclinical studies. The review was registered with PROSPERO before data were abstracted.

Two independent reviewers (D.P.D.W. and A.K.) abstracted data (i.e., study reference; study design; patient characteristics; HDFN treatment patterns; clinical outcomes [eg, fetal anemia, hydrops fetalis, and adverse events]; intravenous immunoglobulin [IVIG] efficacy; mortality; and prevalence) from studies that fulfilled inclusion and exclusion criteria. All abstracted data underwent quality control by the project director (D.O.), who screened 10% of included/excluded articles. The methodological quality (risk of bias) of the selected studies was assessed by 2 independent reviewers (D.P.D.W. and A.K.) using the JBI Critical Appraisal Checklist for Case Reports [ 18 ], the JBI Critical Appraisal Checklist for Case Series [ 19 ], the Newcastle-Ottawa Scale for retrospective and prospective cohort studies [ 20 ], the Checklist for Reporting Results of Internet E-Surveys (CHERRIES) for questionnaires [ 21 ], and lastly the NICE checklist for randomized controlled trials (RCTs).

Data from eligible studies were characterized as representative, which included data from studies that accurately reflected the characteristics of the larger group (e.g., larger case series, retrospective or prospective studies, RCTs), or were characterized as nonrepresentative, which included data from studies that reflected a small proportion of the characteristics of the larger group (e.g., case reports or small case series, or studies in a subset of the larger group, such as cases treated with IUT or only cases with hydrops fetalis). When possible, we aggregated information reported in a similar manner. For unique outcomes, we highlighted information from generalizable studies. Where appropriate, data were summarized as percentage (mean ± standard deviation [SD] or range) or median (interquartile range [IQR]) for patient groups or patient populations (e.g., Rh[D] or Kell, Rh[D] treated with IVIG or Rh[D] not treated with IVIG). Case reports and case series were excluded from prevalence analyses.

An assessment of the available findings was conducted to identify evidence gaps, and recommendations to fill unmet needs were formulated. Results pertinent to mothers and fetuses are reported herein. Neonatal outcomes will be reported in a separate article.

Humanistic and economic burden

A separate objective of this systematic review is to determine the humanistic and economic burden of HDFN. We conducted a systematic search using the same criteria as previously mentioned (Additional file 2 : Appendix S2). We selected studies reporting on quality of life, humanistic burden, economic burden, health care resource use, and direct and indirect costs. The review process was performed according to the PRISMA and MOOSE guidelines and similar as previously stated.

Data sources

In addition to the 2,538 articles identified through searches of MEDLINE and EMBASE, we identified 3 articles from our personal libraries (Fig.  1 ). The search on ClinicalTrials.gov did not yield any additional results to the search on MEDLINE and EMBASE. Overall, 2,363 of the 2,541 total articles were excluded on the basis of title and abstract review, and 119 were excluded on the basis of full-text review. Besides the 59 articles that remained, we identified 1 article from a review of applicable systematic reviews of cohort studies.

Study characteristics

Among the 60 eligible studies that were included in our analysis (Table S 1 ), [ 2 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ] nearly half were retrospective cohort studies ( n  = 27 [45%]), followed by case reports and case series ( n  = 21 [35%]), prospective cohort studies ( n  = 7 [12%]), observational cohort studies ( n  = 3 [5%]), and RCTs and questionnaires ( n  = 1 [2%] each). More studies included patients with only Rh(D)-mediated HDFN ( n  = 26) than only K-mediated HDFN ( n  = 7); 27 studies included patients with Rh(D)- or K-mediated HDFN. Studies were conducted across 25 countries, most commonly The Netherlands ( n  = 12), followed by Turkey and the United States ( n  = 6 each). The 60 studies comprised 146 patient groups, including mothers, neonates, and fetuses. Of these patient groups, 46 were single patients extracted from case reports. Mean (range) group size, including case reports, was 36.5 (SD ± 68.7, range 1.0–334.0). The reported patient groups included cases managed between 1985 and 2019.

Methodological quality of the studies

Of the 14 included case reports, 7 received a perfect score (8/8) using the JBI Critical Appraisal Checklist for Case Reports. Median score among case reports was 7.5 [IQR: 6.0–8.0]. Two of the seven included case series received a perfect score among the applicable questions. Median score among case series was 5.0 [IQR: 5.0–8.5]. Twenty-one of 30 retrospective cohort studies were rated as good quality, 8 as fair, and 1 as poor. All 8 included prospective studies were rated as good quality. The randomized controlled trial by Santos et al. was rated as having low risk of bias in all 4 domains—selection bias, performance bias, attrition bias, and detection bias. Tables S 4 a-e contains a detailed overview of the methodological quality of the selected studies.

Diagnostic testing

Diagnostic testing data were available for 59 of the 60 studies. The most commonly reported diagnostic testing method was ultrasound ( n  = 20; median [IQR]: 100% [100–100%]), followed by percutaneous umbilical cord sampling ( n  = 17; 100% [100–100%]); anti-D and/or anti-K antibody titer ( n  = 16; 100% [100–100%]); fetal hemoglobin ( n  = 15; 100% [100–100%]); Coombs/antiglobulin testing ( n  = 15; 100%); cell-free DNA testing ( n  = 8; 100% [80–100%]); amniocentesis ( n  = 7; 100% [50–100%]); free antibody testing, antibody release testing, and gel card technique ( n  = 2; 100%); and magnetic resonance imaging ( n  = 2; 100% [56.5–100%]).

Prevalence of D- and K-mediated HDFN

The mean ± SD prevalence of Rh(D)-mediated HDFN (requiring any form of treatment) as reported in 5 studies [ 23 , 29 , 45 , 47 , 54 ] was 0.047%±0.037% among all pregnancies that were managed and delivered in the centers of the 5 selected studies (Fig.  2 ). The reported prevalence of K-mediated HDFN (requiring any form of treatment) among all pregnancies managed and delivered in the centers reporting in 2 retrospective studies was 0.006% [ 45 , 47 ]. No data were available for the prevalence of early-onset HDFN (requiring intervention before 24 weeks of pregnancy) in the selected studies. The gestational age at first IUT was between 25 and 27 weeksand the mean gestational age at birth between 34 and 36 weeks (Table  1 ) amongst all selected studies [ 2 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ].

Prevalence of Rh(D)-mediated HDFN (Requiring a Form of Treatment) Among All Referred Pregnancies [ 18 , 24 , 40 , 42 , 49 ]. D, Rh(D); HDFN, hemolytic disease of the fetus and newborn; Rh, Rhesus; SD, standard deviation

Frequencies of antenatal management strategies

Antenatal treatment data were available for 24 studies (Table S 8 ) [ 24 , 25 , 29 , 30 , 33 , 34 , 35 , 36 , 37 , 42 , 43 , 48 , 51 , 52 , 56 , 58 , 59 , 60 , 61 , 62 , 63 , 65 , 71 , 80 ]. The most commonly reported antenatal treatment across these studies was IUT ( n  = 9 with representative data [ 25 , 29 , 33 , 36 , 37 , 56 , 59 , 60 , 65 ]; n  = 3 with nonrepresentative data [ 35 , 58 , 62 ].

Intrauterine transfusions

Among the 9 studies with representative data, IUTs were given at a median frequency of 13.0% (IQR: 7.2–66.0) among pregnancies with a positive anti-Rh(D) screening that were monitored prenatally with ultrasonography. Three of these studies monitored pregnancies with a positive anti-Rh(D) screening and a risk-stratification using the antibody titers and/or antibody-dependent cellular cytotoxicity values above cut-off value, and might therefore overestimate the frequency of IUTs [ 56 , 59 , 60 ]. In these three studies, the frequency of IUTs was 64.7% (range 59.2–66) [ 56 , 59 , 60 ]. Number of IUTs was reported by only two of these studies with a median of 2 (range 0–4) [ 56 , 59 ]. IUTs were required in 76.8% of pregnancies, as reported in 63/82 collective cases [ 36 , 56 , 60 ].

The frequency of IUTs in pregnancies with a positive anti-Rh(D) screening monitored without serological cut-off values was 11.2% (range, 4.5–58.6) in the collective cases (42/376) reported by 5 studies [ 25 , 29 , 33 , 37 , 65 ]. The number of IUTs required was only reported by 1 study with a mean of 2.4 (SD not reported) [ 33 ]. Data on the need for IUTs in pregnancies with K-alloimmunization without serological cut-offs were reported by 1 study and was 12.5% in 1/8 reported cases [ 25 ].

Alternative management strategies

Use of IVIG alone was reported in 1 study with representative data [ 48 ]. In this case series of 3 severely affected pregnancies, 2 (Rh[D], n  = 1; Kell, n = 1) resulted in live births without IUT; the third (Rh[D] + anti-C) was treated with IUT but resulted in a post-procedure intrauterine death.

Use of IUT + IVIG was reported in 4 studies ( n  = 1 with representative data[ 61 ]; n  = 3 with nonrepresentative data [ 35 , 42 , 62 ]). In the one study with representative data, 3.2% of the Rh(D) alloimmunization cases and 4.3% of the Kell alloimmunization cases were treated with IUT + IVIG [ 61 ].

Use of other treatments (therapeutic plasma exchange [TPE]; maternal plasma exchange ± high-dose IVIG; TPE + IVIG + IUT; TPE + immunoadsorption + IVIG + IUT; plasmapheresis + IUT; and plasmapheresis + IVIG + IUT) were reported in 10 studies with a total of 38 cases [ 24 , 30 , 34 , 36 , 43 , 51 , 52 , 63 , 71 , 80 ]. Plasmapheresis + IVIG + IUT was the most commonly reported treatment regimen across these 10 studies.Two of these studies did not report gestational age at start of the treatment, at first IUT (if applicable) and at birth [ 36 , 80 ]. The remaining 8 studies, including 20 cases total, reported the mean gestational age at treatment initiation (13.0 ± 5.7 weeks). 17/20 cases required an IUT for fetal anemia. The mean gestational age at first IUT was 24.2 ± 3.1 weeks, with a median of 4 IUTs (range 1–8) administered. Gestational age at birth was 34.4 ± 3.1 weeks [ 30 , 34 , 43 , 51 , 52 , 63 , 71 ]. In the series of 20 cases, one patient received plasmapheresis, which was started a week after the first IUT at a gestational age of 27 weeks [ 43 ]. In all other cases, the alternative treatment was started prior to the occurrence of fetal anemia. The indications to start the alternative treatment option in the 20 cases were previous intrauterine fetal death ( n  = 11), neonatal hydrops fetalis and/or death ( n  = 4), marked elevation in antibody titer ( n  = 4), and suspected fetal anemia after initial IUT ( n  = 1).

Clinical outcomes of mothers and fetuses

The most commonly reported maternal/fetal clinical outcome across studies was hydrops fetalis ( n  = 19 with representative data [ 23 , 28 , 31 , 32 , 41 , 42 , 47 , 49 , 51 , 53 , 59 , 64 , 66 , 67 , 69 , 75 , 76 , 79 , 80 ] (Table S 8 ); n  = 10 with nonrepresentative data [ 24 , 39 , 40 , 44 , 46 , 52 , 55 , 68 , 70 , 74 ]). The rate of hydrops fetalis among pregnancies with Rh(D)-mediated HDFN treated with IUT was 14.9% (range, 0–50%) in 72/483 reported cases [ 31 , 32 , 49 , 53 , 66 , 76 , 79 ]. The rate of hydrops fetalis among pregnancies with K-mediated HDFN treated with IUT was 39.2% in 49/125 reported cases [ 69 , 75 , 76 , 79 ]. Five studies reported on the rate of hydrops fetalis in all pregnancies monitored for Rh(D)- and or K-alloimmunization, with or without the need for antenatal treatment. The rate of hydrops fetalis in these studies was 7.3% in 17/232 collective cases.

Severe fetal anemia was reported in 1 study with representative data [ 28 ] (Table S 8 ) and 11 studies with nonrepresentative data [ 30 , 39 , 42 , 43 , 44 , 46 , 52 , 63 , 68 , 74 , 80 ]. In the 1 cohort study with representative data, 100% of 22 successful IUTs performed in Rh(D)- or K-mediated HDFN cases within 20 weeks of gestation were considered severely anemic (≥ 5 SDs from the fetal hemoglobin reference value of 15 g/dL; 1 SD = 1 g/dL difference from reference value) [ 28 ]. Adverse events or procedure-related complications were commonly reported after IUTs or other treatments for Rh(D)- and/or K-mediated HDFN ( n  = 11 studies with representative data [ 28 , 33 , 47 , 51 , 53 , 63 , 64 , 66 , 69 , 72 , 80 ] (Table S 8 ); n  = 2 studies with nonrepresentative data [ 68 , 73 ]). Bradycardia was the most frequently reported post-IUT complication per procedure, and adverse serological outcomes were the most frequently reported post-IUT complication per fetus, although adverse serological outcomes were reported in only 1 study [ 33 ] (Fig. S 2 ).

IVIG efficacy

Assessment of IVIG efficacy in women and fetuses affected by HDFN was based on treatment response in 6 studies [ 24 , 30 , 34 , 48 , 62 , 80 ] and associated mortality in 3 studies [ 35 , 42 , 63 ] (Table S 8 ). Collectively, findings indicate that IVIG delayed or prevented IUT. IVIG-associated fetal mortality ranged from 0 to 50% across the 3 studies reporting this outcome [ 35 , 42 , 63 ].

Fetal mortality

The overall mean ± SD fetal mortality rate was 19.8% ± 29.4% across 19 studies, including representative case reports [ 28 , 31 , 35 , 42 , 43 , 45 , 47 , 49 , 53 , 63 , 64 , 66 , 68 , 69 , 73 , 75 , 76 , 78 , 80 ] (Table S 8 ). Head-to-head comparison of mortality rates between the different treatment strategies is limited by variation in potential patient characteristics between the groups. Employed treatment strategies for HDFN take into account previous obstetrical history, for example 75% of cases in the “IUT + other” group had a history of fetal or neonatal death due to HDFN. Together, these will influence the outcomes of HDFN in the current pregnancy and limit our capability of mortality rate comparison.

In addition to the 1457 articles identified in the systematic search, one additional article was identified from personal libraries (Fig. S 2 ). Based on the title/abstract screening 1435 articles were excluded. Full-text screening was performed in the remaining 23 records of which 22 were excluded. Healthcare utilization was reported by only one study with a median of duration of phototherapy of 4-4.5 days and a median length of stay of 6.5–7.5 days [ 65 ].

Main findings

We found that the prenatal burden and need for treatment remains relatively high – we estimated that 13% of pregnancies monitored for Rh(D) or K-alloimmunization required one or more IUTs – despite advances in the identification and care for pregnancies at risk of HDFN. Strikingly, the rate of hydrops fetalis in pregnancies requiring an IUT was found to be 14.9% for Rh(D)-mediated HDFN and 39.2% in K-mediated HDFN. As the occurrence of hydrops fetalis was previously found to be associated with impaired neurodevelopmental outcomes [ 81 ] still much is to gain in the timely identification of pregnancies at-risk and the timely detection and treatment of fetal anemia to prevent hydrops fetalis. The average gestational age at first IUT was 27 weeks, which was possibly delayed by using IVIG and/or plasmapheresis although evidence on this in the included studies is limited. Although IUT is a regarded as a relatively safe procedure in experienced hands, its invasive nature still poses serious risks to the mother and fetus. Fetal loss rate increases when procedures need to be done early in gestation (i.e., < 22 weeks) [ 13 ]. It is also noteworthy that the average gestational age at birth in the present analyses was approximately 35 weeks for Rh(D)- and/or K-mediated HDFN, which is considered late preterm and might also represent that early delivery is frequently employed in the management of pregnancies at risk of fetal anemia although we were unable to extract data on this from the included studies. But, late preterm birth has the potential for serious consequences, such as increased risk for short- or long-term respiratory issues [ 82 , 83 , 84 ], readmission [ 82 ], death [ 82 , 84 , 85 ], and neurocognitive impairment in late adulthood [ 86 , 87 ].

Strengths and limitations

A strength of this systematic review and corresponding analyses is the minimal limitation on study design criteria. Overall, 35% of the studies included in our analyses were case reports or case series, validating the rarity of HDFN. By including case reports and case series, we were able to identify and aggregate data on treatment types (e.g., plasmapheresis and plasma exchange) that were not typically reported in larger cohort studies. But, inclusion of case reports and case series might also be regarded as a limitation as it may skew and overestimate the results as, given the rarity of HDFN, the most severe cases are generally reported in literature. Our estimates might therefore not truly mirror the population level data.

Also, we were unable to quantify heterogeneity (using e.g. the I 2 -statistic) due to the descriptive nature of this systematic review and consequent lack of reported comparisons between interventions. However, a certain level of heterogeneity may be expected due to differences in available management options, treatment protocols, prevalence of Rh(D)- and K-negativity, geographical location and sociodemographic differences. These differences may be approached by the varying frequencies of, for instance, IUTs and rate of hydrops fetalis between included studies.

Our analyses are further limited by the strict prespecified inclusion of only Rh(D)- or K-mediated HDFN populations. By applying this criterion, 7 studies were excluded from analyses—despite high quality of evidence and outcomes of interest—because Rh(c) populations were mixed with Rh(D) or Kell populations, or the population was not well defined [ 88 , 89 , 90 , 91 , 92 , 93 , 94 ]. We were unable to stratify the data per alloimmunization type with the data provided in these articles. One of these studies represented the only prospective study with long-term outcomes [ 89 ], thereby also indicating the lack of data on long-term outcomes and the need for further research on the topic.

Interpretation

Almost all studies included in these analyses were conducted in high-income countries, which have adequate resources for screening, prophylaxis and preventative measures for alloimmunization, and referral to specialized fetal therapy centers. Outcome data on HDFN-complicated pregnancies from less privileged or less organized societies are lacking and, if analyzed, likely are less favorable. This well-known bias in outcome reporting indicates an important evidence gap and signifies the need for international collaboration to gain a better understanding of the global burden of HDFN and to pave the way for potential wide-spread improvements. To add to that, we also found that the evidence for frequency of use and effectiveness of alternative treatment options such as IVIG, plasmapheresis, and plasma exchange on disease severity and the prevention of fetal anemia is limited in the included studies. Also, as previously mentioned it is likely that the most severe cases are reported in literature due to the rarity of the disease. Taken together, future research should aim to gain more exact insight into the employed treatment options and its efficacy and clinical outcomes of mothers, fetuses, and neonates affected by HDFN through an international retrospective and/or prospective registry through the collection of data on diagnostics, antenatal and postnatal treatments and short- and long-term clinical outcomes of mothers, fetuses, and neonates. Such an international effort will pave the way for long sought after answers.

A separate objective of this systematic review, as previously mentioned, was to ascertain the economic and humanistic burden of HDFN. However, through the systematic approach only one study reporting on healthcare utilization was included. This dearth of information indicates another major gap in knowledge, particularly as it relates to the impact of HDFN on a pregnant individual’s quality of life and the potential downstream consequences of high-risk pregnancy on family planning decisions, as well as on the healthcare system.

To conclude, we found that the clinical burden of Rh(D)- and K-mediated HDFN remains relatively high, with 13% of pregnancies monitored for Rh(D)- or K-alloimmunization requiring an IUT and most births occurring at a late preterm gestational age. We identified several important evidence gaps that provide opportunities for future studies to further improve the clinical care of HDFN.

Availability of data and materials

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Abbreviations

• Hemolytic disease of the fetus and newborn

Checklist for Reporting Results of Internet E-Surveys

Deoxyribonucleic acid

Interquartile range

• Intrauterine transfusion

Intravenous immunoglobulins

Joanna Briggs Institute

Meta-analysis of Observational Studies in Epidemiology

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Randomized controlled trial

Standard deviation

Therapeutic plasma exchange

United States of America

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Acknowledgements

Dipen Patel and Chandrasekhar Boya of OPEN Health contributed to this work. Medical writing and editorial support were provided by Maribeth Bogush, PhD, of Peloton Advantage, LLC, an OPEN Health company, in accordance with Good Publication Practice (GPP3) guidelines, and funded by Janssen Pharmaceuticals.

Systematic review registration

PROSPERO 2021 CRD42021234940 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021234940 .

Funding for this systematic literature review was provided by Janssen Pharmaceuticals (Raritan, NJ, USA). The authors had access to relevant aggregated study data and other information (e.g., study protocol, analytic plan and report, and validated data tables) required to understand and report research findings. The authors take responsibility for the presentation and publication of the research findings, have been fully involved at all stages of publication and presentation development, and are willing to take public responsibility for all aspects of the work. All individuals included as authors and contributors who made substantial intellectual contributions to the research, data analysis, and publication or presentation development are listed appropriately. The role of the sponsor in the design, execution, analysis, reporting, and funding is fully disclosed. The authors’ personal interests, financial or non-financial, relating to this research and its publication have been disclosed.

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Department of Pediatrics, Division of Neonatology, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, The Netherlands

Derek P. de Winter

Department of Immunohematology Diagnostic Services, Sanquin Diagnostic Services, Amsterdam, The Netherlands

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Allysen Kaminski

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May Lee Tjoa

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Contributions

DPDW, AK, ML, and DO contributed to the study design. AK conducted the search. DPDW and AK independently reviewed eligible studies, extracted data, evaluated the methodological quality, and performed analyses. The manuscript was written by DPDW. DPDW, AK, ML, and DO were involved in revising the manuscript. All authors approved the final version for publication.

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Derek P. de Winter: PhD program funded by Momenta Pharmaceuticals, Inc., which was acquired by Johnson & Johnson; coordinating investigator for a phase 2 trial (NCT03842189) of a new drug for the treatment of HDFN, which is sponsored by Janssen Pharmaceuticals.

Allysen Kaminski: Former employee of OPEN Health, which was retained by Janssen Pharmaceuticals to conduct the study.

May Lee Tjoa: Employee and stockholder of Janssen Pharmaceuticals.

Dick Oepkes: Former principal investigator for a phase 2 trial (NCT03842189) of a new drug for the treatment of HDFN, which is sponsored by Janssen Pharmaceuticals.

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Supplementary Information

Additional file 1: table s1..

General Characteristics of Studies and Patient Groups. Table S2. Research Questions Relevant to Mothers and Fetuses. Table S3. Inclusion and Exclusion Criteria a . Table S4a. Methodologic Quality of Selected Case Reports. Table S4b. Methodologic Quality of Selected Case Series. Table S4c. Methodologic Quality of Selected Retrospective Cohort Studies. Table S4d. Methodologic Quality of Selected Prospective Cohort Studies. Table S4e. Methodologic Quality of Bennardello et al (25). Table S5. Antenatal Treatments Reported in Studies With Representative Data. Table S6. Hydrops Fetalis, Severe Fetal Anemia, and Adverse Events/Complications Reported in Studies With Representative Data. Table S7. IVIG Treatment Response and Associated Mortality. Table S8. Overall Fetal Mortality Associated With HDFN. Figure S1. Mean Rate of Procedure-related Complications After IUT (Per Procedure [A] and Per Fetus [B]). 12,26,30,32,43,44,46,49,52,60 CS, cesarean section; IUT, intrauterine transfusion; PROM, preterm rupture of membranes. a Adverse serological outcome was defined as the development of additional maternal antibodies to anti-D and/or a ≥4-fold enhancement of antibody titer. 12 . Figure S2. Flowchart of the Article Selection Process for the Humanistic and Economic Burden. SLR, systematic literature review. *From authors’ personal library. †From eligible SLRs of cohort studies.

Additional file 2: Appendix S1.

Search Strategy. Appendix S2. Search Strategy for the Humanistic and Economic Burden. 

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de Winter, D.P., Kaminski, A., Tjoa, M.L. et al. Hemolytic disease of the fetus and newborn: systematic literature review of the antenatal landscape. BMC Pregnancy Childbirth 23 , 12 (2023). https://doi.org/10.1186/s12884-022-05329-z

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DOI : https://doi.org/10.1186/s12884-022-05329-z

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Hemolytic disease of newborn

Aug 25, 2014

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Hemolytic disease of newborn. Objectives. Definition &amp; characteristics ABO vs Rh hemolytic disease of the newborn Pathogenesis Incidence Blood types of mother and baby Severity of disease Laboratory data Prevention Rh immune globulin Tests for feto-maternal hemorrhage

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• incomplete antibody
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• fetomaternal hemorrhage maternal antibodies
• red blood cell hemolysis
• fetal blood

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Objectives • Definition & characteristics • ABO vs Rh hemolytic disease of the newborn • Pathogenesis • Incidence • Blood types of mother and baby • Severity of disease • Laboratory data • Prevention • Rh immune globulin • Tests for feto-maternal hemorrhage • Exchange transfusion protocol

Hemolytic disease of newborn Hemolytic disease of the new born and fetus (HDN) is a destruction of the red blood cells (RBCs) of the fetus and neonate by antibodies produced by the mother It is a condition in which the life span of the fetal/neonatal red cells is shortened due to maternal allo-antibodies against red cell antigens acquired from the father

Antibodies • Five classes of antibodies • IgM • IgG • IgA • IgD • IgE • Blood groups specific antibodies are • IgG and • IgM

Biochemistry of antibodies • Made from four polypeptide chains • Two light (L) chains • Two identical heavy (H) chains • Each class has immunologically distinct heavy chain

Biochemistry of antibodies

Blood group antibodies • Blood group antibodies can be classified as • Naturally occurring and immune antibodies • Depending on presensitization • Cold and warm antibodies • Thermal range of antibodies • Most natural Abs are cold & some e.g wide thermal range like Anti A and Anti B • Most immune Abs are warm and can destroy red cell in-vivo • Complete and incomplete antibodies • Depends on agglutination of saline suspended red cells • IgM is complete antibody; most naturally occurring antibodies are complete and of IgM class • IgG is incomplete antibody

Antibodies of ABO system • Anti- A • Naturally occurring • Immune • Anti- B • Naturally occurring • Immune • Anti- A1 • Anti- H

Antibodies of Rh system • Naturally occurring • Anti- E • Occasionally anti-D and anti C • Immune antibodies • D antibodies are more immunogenic • Other are anti c, E, e, C. • Most common is anti- E • After anti- D, anti- c is the common cause of HDN (The vast majority of Rh antibodies are IgG and do not fix complement)

Antibodies from other blood group systems • Anti- K • Kell blood group system • Usually is immune antibody • Warm Ab • Anti- Jka • Kidd blood group system • Usually is immune antibody • Warm Ab

Complement • Complements are series of proteins, present in plasma as an inactive precursors • When activated and react sequentially with each other they mediate destruction of cells and bacteria • Complement activation involves two stages • Opsonization • Lytic stage

Complement • Antibodies can fix complement and cause rapid destruction of red cells • Destruction depends on the amount of antibody and complement • In ABO- incompatible transfusion no surviving A or B red cells can be seen after 1 hour of transfusion • Why? • Remember naturally occurring Abs. are IgM and fix complement mediating the hemolysis

Disease mechanism - HDN • There is destruction of the RBCs of the fetus by antibodies produced by mother • If the fetal red cells contains the corresponding antigen, then binding of antibody will occur to red cells • Coated RBCs are removed by mononuclear phagocytic system

Neonatal liver is immature and unable to handle bilirubin Unconjugated bilirubin Conjugated bilirubin Coated red blood cell are hemolysed in spleen

Pathogenesis; before birth

Pathogenesis; after delivery

Clinical features • Less severe form • Mild anemia • Severe forms • Icterus gravis neonatorum (Kernicterus) • Intrauterine death • Hydrops fetalis • Oedematous, ascites, bulky swollen & friable placenta • Pathophysiology • Extravascular hemolysis with extramedullary erythropoiesis • Hepatic and cardiac failure

Hemolytic disease of newborn HDN BOFORE BIRTH • Anemia (destruction of red cells) • Heart failure • Fetal death AFTER BIRTH • Anemia (destruction of red cells) • Heart failure • Build up of bilirubin • Kernicterus • Severe growth retardation

P N Blood film of a fetus affected by HDN showing polychromasia and increased number of normaoblasts

Rh HEMOLYTIC DISEASE OF NEWBORN • Antibodies against • Anti-D and less commonly anti-c, anti-E • Mother is the case of anti-D is Rh -ve (negative) • Firstborn infant is usually unaffected • Sensitization of mother occurs • During gestation • At the time of birth • All subsequent offspring inheriting D-antigen will be affected in case of anti-D HDN

Pathogenesis Fetomaternal Hemorrhage Maternal Antibodies formed against Paternally derived antigens During subsequent pregnancy, placental passage of maternal IgG antibodies Maternal antibody attaches to fetal red blood cells Fetal red blood cell hemolysis

Diagnosis and Management • Cooperation between • Pregnant patient • Obstetrician • Her spouse • Clinical laboratory

Recommended obstetric practice • History; including H/O previous pregnancies or and disease needing blood transfusion • ABO and Rh testing • Antibody detection; • To detect clinically significant IgG Ab which reacts at 370C • Repeat testing required at 24 or 28 weeks if first test negative • Antibody specificity • Parental phenotype • Amniocyte testing

Antibody titres • Difference of 2 dilutions or score more than 10 is significant • Amniocentesis and cordocentesis • Concentration of bilirubin • Spectrophotometric scan • Indirect method • Increasing or un-change OD as pregnancy advance shows worsening of the fetal hemolytic disease • Fetal blood sample can be taken and tested for • Hb, HCT, blood type and DCT (Direct Coombs test) Percutaneous Umbilical blood sampling

Prevention of Rh- HDN • Prevention of active immunization • Administration of corresponding RBC antibody (e.g anti-D) • Use of high-titered Rh-Ig (Rhogam) • Calculation of the dose • Kleihauer test for fetal Hb

Mechanism of action • Administered antibodies will bind the fetal Rh- positive cells • Spleen captured these cells by Fc-receptors • Spleen remove anti-D coated red cells prior to contact with antigen presenting cells “antigen deviation”

The Kleihauer test • The identification of cells containing haemoglobin F depends on the fact that they resist acid elution to a greater extent than do normal cells, they appear as isolated, darkly stained cells among a background of palely staining ghost cells. • The occasional cells that stain to an intermediate degree are less easy to evaluate; some may be reticulocytes because these also resist acid elution to some extent.

ABO HEMOLYTIC DISEASE OF NEW BORN • For practical purpose, only group O individuals make high titres IgG • Anti-A and anti-B are predominantly IgM • ABO antibodies are present in the sera of all individuals whose RBCs lack the corresponding antigens

ABO HDN contd. • Signs and symptoms • Two mechanism protects the fetus against anti-A and anti-B • Relative weak A and B antigens o fetal red cells • Widespread distribution of A & B antigen in fetal tissue diverting antibodies away from fetal RBCs • Anemia is most of the time mild • ABO- HDN may be seen in the first pregnancy • Laboratory findings • Differ from Rh- HDN; microspherocytes are characteristic of ABO- HDN • Bilirubin peak is later; 1- 3 days after birth • Collection of cord blood and testing eluates form red cells will reveal anti-A or anti-B • Treatment • Group O donor blood for exchange transfusion which is rarely required

HDN- due to other antibodies • Anti-c • Usually less severe than that cause by Anti-D • Anti-K • May cause severe fetal anemia • Blood transfusion for the treatment should lack the appropriate antigen

Summary. • Hemolytic disease of newborn occurs when IgG antibodies produced by the mother against the corresponding antigen which is absent in her, crosses the placenta and destroy the red blood cells of the fetus. • Proper early management of Rh- HDN saves lives of a child and future pregnancies • ABO- HDN is usually mild • Other blood group antigens can also cause HDN

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Unique molecular properties of nipocalimab enabling differentiated potential in treating generalized myasthenia gravis to be presented at American Academy of Neurology’s 2024 Annual Meeting

Analysis of clinical and non-clinical studies supports the investigational treatment’s potential for rapid, deep and sustained immunoglobulin g (igg) lowering.

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DENVER, Co. (April 11, 2024) – Johnson & Johnson today announced the planned presentation of new non-clinical studies underscoring the molecular properties of nipocalimab, an investigational fully human monoclonal antibody targeting the neonatal fragment crystallizable receptor (FcRn). These data showcase the promise of nipocalimab as a potential best-in-class FcRn blocker and unique characteristics including its high binding affinity and specificity to the immunoglobulin G (IgG) binding site of FcRn. 1 These properties, along with the dosing regimen chosen for study contribute to its dose- and time-dependent receptor occupancy, resulting in the rapid, deep and sustained lowering of IgG, including IgG autoantibodies in neuroimmune diseases such as generalized myasthenia gravis (gMG) and other autoantibody-driven diseases. 1 The data will be one of six scientific posters the Company will present at the American Academy of Neurology’s (AAN) 2024 Annual Meeting ( Poster 14-008 ).

gMG is a highly debilitating, rare autoantibody-driven disease for which there currently is no cure, characterized by fluctuating weakness of the skeletal muscles leading to symptoms like difficulty speaking and swallowing. 1 A Phase 2 clinical study with nipocalimab published in Neurology (2024) demonstrated MG patients with a greater magnitude of IgG lowering tended to have greater improvements in key efficacy outcomes (e.g., MG-ADL a ). 2

“These new data offer additional evidence for the potential of nipocalimab to deliver optimized treatment outcomes for autoantibody-driven neurological diseases like gMG,” said Sindhu Ramchandren, M.D., Clinical Development Leader, Neuroscience, Johnson & Johnson Innovative Medicine. “A significant unmet need remains for more effective treatments able to offer sustained disease control in gMG. We are encouraged by the potential of nipocalimab as a uniquely engineered treatment with characteristics which may address this gap for people living with this chronic, debilitating disease.”

Nipocalimab is the only FcRn blocker being studied across three key segments of auto- and alloantibody driven diseases, including Maternal Fetal, Rare Autoantibody and Prevalent Rheumatology. 1 Within the past year nipocalimab has demonstrated clinical effect in four autoantibody-driven diseases across all three segments: hemolytic disease of the fetus and newborn in Maternal Fetal, gMG in Rare Autoantibody, and Sjögren’s disease and rheumatoid arthritis in Prevalent Rheumatology. Nipocalimab exhibits non-pH-dependent, high binding affinity, enabling it to decrease maternal circulating IgG levels and block maternal to fetal IgG transfer with minimal evidence of transplacental transfer to the fetus. These properties contribute to the position of nipocalimab as the only FcRn blocker being studied in maternal fetal indications. 1 Not only are these indications of high unmet medical need, but generating data in pregnancy is differentiating because approximately 80 percent of patients living with autoantibody-driven diseases are female, and up to half are of childbearing potential. 3,4

“We are pleased to present new data for nipocalimab at the AAN 2024 Annual Meeting underscoring our unwavering pursuit of best-in-class treatments for autoantibody diseases,” said Katie Abouzahr, M.D., Vice President, Autoantibody and Maternal Fetal Immunology Disease Area Leader, Johnson & Johnson Innovative Medicine. “We are committed to leveraging our neuroscience and immunology expertise, understanding of immune-mediated disease, and comprehensive studies of nipocalimab to potentially deliver transformative therapies that may result in sustained symptom-free remission for patients.”

Nipocalimab was granted Fast Track designation in HDFN and warm autoimmune hemolytic anemia (wAIHA) in July 2019, gMG in December 2021 and fetal neonatal alloimmune thrombocytopenia (FNAIT) in March 2024 and was granted orphan drug status for wAIHA in December 2019, HDFN in June 2020, gMG in February 2021, chronic inflammatory demyelinating polyneuropathy (CIDP) in October 2021 and FNAIT in December 2023 by the U.S. Food and Drug Administration (FDA). The investigational treatment for HDFN was also granted Breakthrough Therapy Designation by the FDA in February 2024, and orphan medicinal product designation by the European Medicines Agency in October 2019.

Editor’s Notes: a. MG-ADL (Myasthenia Gravis – Activities of Daily Living) provides a rapid clinical assessment of the patient’s recall of symptoms impacting activities of daily living, with a total score range of 0 to 24; a higher score indicates greater symptom severity.

About generalized myasthenia gravis (gMG) Myasthenia gravis (MG) is an autoantibody disease where autoantibodies target proteins at the neuromuscular junction, disrupt neuromuscular signaling, and impair or prevent muscle contraction. 5 The disease impacts an estimated 700,000 people worldwide, with 85% of these patients experiencing the more extensive form of the disease, gMG. 5 In MG, the immune system mistakenly attacks muscle receptors by producing anti-receptor antibodies (e.g.,anti-acetylcholine receptor [AChR], anti-muscle-specific kinase [MuSK] or anti-low density lipoprotein-related protein 4 [LRP4]) that can block or destroy these muscle receptors, preventing signals from transferring from nerves to muscles. 6 Symptoms include limb weakness, drooping eyelids, double vision, and difficulties with chewing, swallowing, speech, and breathing. 7,8 Although gMG may be managed with current therapies, research is needed to develop new treatments for those who may not respond well enough to or tolerate current therapies.

About nipocalimab Nipocalimab is an investigational, high-affinity, fully human, aglycosylated, effectorless, monoclonal antibody that aims to selectively block FcRn to reduce levels of circulating immunoglobulin G (IgG antibodies, including autoantibodies and alloantibodies that underlie multiple conditions. 9 Nipocalimab is the only FcRn blocker being studied across three key segments in the autoantibody space: Rare Autoantibody diseases (e.g., generalized myasthenia gravis in adults and children, chronic inflammatory demyelinating polyneuropathy, warm autoimmune hemolytic anemia, and idiopathic inflammatory myopathies); Maternal Fetal diseases mediated by maternal alloantibodies (e.g., hemolytic disease of the fetus and newborn and fetal and neonatal alloimmune thrombocytopenia); and Prevalent Rheumatology (e.g., rheumatoid arthritis, Sjögren’s disease, and systemic lupus erythematosus). 10,11,12,13,14,15,16,17,18 Blockade of FcRn has the potential to reduce overall IgG including pathogenic alloantibody levels while preserving immune function without causing broad immunosuppression. Blockade of IgG binding to FcRn in the placenta is also believed to prevent transplacental transfer of maternal alloantibodies to the fetus. 19,20

About Johnson & Johnson At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity.

Learn more at https://www.jnj.com/ or at www.janssen.com/johnson-johnson-innovative-medicine .

Follow us at @JanssenUS and @JNJInnovMed .

Janssen Research & Development, LLC and Janssen Biotech, Inc. are both Johnson & Johnson companies.

Cautions Concerning Forward-Looking Statements This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of nipocalimab. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC, Janssen Biotech, Inc. and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behavior and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in Johnson & Johnson’s subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov, www.jnj.com or on request from Johnson & Johnson. None of Janssen Research & Development, LLC, Janssen Biotech, Inc. nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

1 Nilufer Seth, et al. Nipocalimab a High Affinity, Immunoselective Clinical FcRn Blocker with Unique Properties: Observations from Non-clinical and Clinical Studies. 2024.

2 “Johnson & Johnson Reports Positive Topline Results for Nipocalimab from a Phase 3 Pivotal Study in Generalized Myasthenia Gravis (GMG) and a Phase 2 Study in Sjögren’s Disease (SJD).” JNJ.com, February 13, 2024.

3 Angum, Fariha et al. Cureus vol. 12,5 e8094. 13 May. 2020, DOI:10.7759/cureus.8094

4 Johnson & Johnson data on file

5 Chen J, Tian D-C, Zhang C, et al. Incidence, mortality, and economic burden of myasthenia gravis in China: A nationwide population-based study. The Lancet Regional Health - Western Pacific. 2020;5(100063). https://doi.org/10.1016/j.lanwpc.2020.100063 .

6 Wiendl, H., et al., Guideline for the management of myasthenic syndromes. Therapeutic advances in neurological disorders, 16, 17562864231213240. https://doi.org/10.1177/17562864231213240 . Last Accessed April 2024.

7 Myasthenia gravis fact sheet. Retrieved April 2024 from https://www.ninds.nih.gov/sites/default/files/migrate-documents/myasthenia_gravis_e_march_2020_508c.pdf .

8 Myasthenia Gravis: Treatment & Symptoms. (2021, April 7). Retrieved April 2024 from https://my.clevelandclinic.org/health/diseases/17252-myasthenia-gravis-mg .

9 ClinicalTrials.gov. NCT03842189. Available at: https://clinicaltrials.gov/ct2/show/NCT03842189 . Last accessed: April 2024

10 de Winter DP, Kaminski A, et al. Hemolytic disease of the fetus and newborn: systematic literature review of the antenatal landscape. BMC Pregnancy and Childbirth. 2023;23(12). DOI: https://doi.org/10.1186/s12884-022-05329-z . Last accessed: April 2024.

11 ClinicalTrials.gov Identifier: NCT05265273. Available at: https://clinicaltrials.gov/ct2/show/NCT05265273 . Last accessed: April 2024.

12 ClinicalTrials.gov Identifier: NCT04951622. Available at: https://clinicaltrials.gov/ct2/show/NCT04951622 . Last accessed: April 2024.

13 ClinicalTrials.gov Identifier: NCT05327114. Available at: https://clinicaltrials.gov/ct2/show/NCT05327114 . Last accessed: April 2024.

14 ClinicalTrials.gov Identifier: NCT04119050. Available at: https://clinicaltrials.gov/ct2/show/NCT04119050 . Last accessed: April 2024.

15 ClinicalTrials.gov Identifier: NCT04968912. Available at: https://clinicaltrials.gov/ct2/show/NCT04968912 . Last accessed: April 2024.

16 ClinicalTrials.gov Identifier: NCT04882878. Available at: https://clinicaltrials.gov/ct2/show/NCT04882878 . Last accessed: April 2024.

17 ClinicalTrials.gov Identifier: NCT05379634. Available at: https://clinicaltrials.gov/ct2/show/NCT05379634 . Last accessed: April 2024.

18 ClinicalTrials.gov Identifier: NCT04991753. Available at: https://clinicaltrials.gov/ct2/show/NCT04991753 . Last accessed: April 2024.

19 Lobato G, Soncini CS. Relationship between obstetric history and Rh(D) alloimmunization severity. Arch Gynecol Obstet. 2008 Mar;277(3):245-8. DOI: 10.1007/s00404-007-0446-x. Last accessed: April 2024.

20 Roy S, Nanovskaya T, Patrikeeva S, et al. M281, an anti-FcRn antibody, inhibits IgG transfer in a human ex vivo placental perfusion model. Am J Obstet Gynecol. 2019;220(5):498 e491-498 e499.

Media contact: Bridget Kimmel Mobile: (215) 688-6033 [email protected]

Investor contact: Raychel Kruper [email protected]