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Year : 2022  |  Volume : 11  |  Issue : 3  |  Page : 172-175

A case of neonatal alloimmune neutropenia with an uncommon presentation

1 Department of Pediatrics, Hospital de Braga, Braga, Portugal
2 Neonatal Intensive Care Unit, Hospital de Braga, Braga, Portugal
3 Department of Hematology, Hematological Diagnosis Unit, Cytometry and Genetics Laboratories, Centro Hospitalar Universitário do Porto, Porto, Portugal

Date of Submission11-Feb-2021
Date of Acceptance13-Nov-2021
Date of Web Publication06-Jul-2022

Correspondence Address:
Marta Ribeiro Silva
Serviço de Pediatria, Hospital de Braga, Braga, Portugal.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcn.jcn_28_21

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Neonatal alloimmune neutropenia (NAN) is a rare condition in neonates, with an incidence of <0.1%. It occurs when maternal antibodies against neutrophil antigens inherited from the father cross the placenta, destroying the neutrophils of the fetus and/or the newborn. We report a case of a female neonate who started exhibiting scattered petechiae over the trunk and lower limbs, a day after birth. The blood count revealed severe neutropenia and mild thrombocytopenia. Infections were excluded. Flow cytometry analysis confirmed the presence of antineutrophil immunoglobulin G antibodies in the newborn's neutrophil membrane and in the mother's serum. When screened for polymorphisms in the genes encoding for human neutrophil antigens (HNA), we identified HNA-1b and/or HNA-3a as potential causes of the mother/daughter incompatibility. Even though neutropenia is usually self-limiting, neonates with NAN are at risk of developing severe infections. Therefore, early identification of these patients can prevent serious complications.

Keywords: Human neutrophil antigens-1b, human neutrophil antigens-3a, neonatal alloimmune neutropenia, neonate, neutropenia

How to cite this article:
Silva MR, Carvalho V, Raposo F, Lima M, Costa M. A case of neonatal alloimmune neutropenia with an uncommon presentation. J Clin Neonatol 2022;11:172-5

How to cite this URL:
Silva MR, Carvalho V, Raposo F, Lima M, Costa M. A case of neonatal alloimmune neutropenia with an uncommon presentation. J Clin Neonatol [serial online] 2022 [cited 2022 Dec 9];11:172-5. Available from: https://www.jcnonweb.com/text.asp?2022/11/3/172/350032

  Introduction Top

Neonatal alloimmune neutropenia (NAN) occurs when maternal immunoglobulin G (IgG) antibodies against antigens of paternal origin present in the fetal neutrophils cross the placenta, causing their destruction.[1],[2] The estimated incidence in neonates is about 0.5–2/1000 live births,[3],[4] and it occurs in 5%–40% of first pregnancies.[1],[2]

A wide variety of antigenic targets have been identified in NAN, but the most common is the human neutrophil alloantigens (HNAs), such as HNA-1a, HNA-1b, and HNA-2a.[1],[5]

At birth, it is common to observe a low absolute neutrophil count (ANC), and it may further decline in the first postnatal week.[2] This low ANC is often self-limited, and its duration can vary from a few weeks to 6 months.[5] During this period, neonates are at high risk of developing severe infections, which are potentially fatal.[3] In most NAN cases, newborns are asymptomatic, and the diagnosis is made as a result of blood analyses performed due to other non-NAN-related conditions.[2] In symptomatic newborns, the most common presentations vary from omphalitis, skin infections, otitis media, and fever of unknown origin, to more severe infections such as pneumonia, meningitis, or sepsis.[1],[2],[5] Severe infections are associated with a 5% of mortality.

Treatment is usually limited to the use of antibiotics to control infections.[1] However, the use of prophylactic antibiotics can be considered in cases of severe neutropenia (ANC <500/μL). In addition, the use of intravenous immunoglobulin (IVIG) and recombinant human granulocyte colony-stimulating factor (G-CSF) can be used to increase the number of neutrophils in neonates suffering from severe infections.[1],[2]

  Case Report Top

A female neonate was born from the second gestation of a healthy 31-year-old mother. The first child had no problems at birth. The parents were cousins in the first degree. The pregnancy was complicated by insulin-controlled gestational diabetes. The mother had a positive indirect Coombs test with anti-JKa and anti-C antibodies, so the newborn was at risk of hemolytic disease. There was no history of blood transfusions.

The delivery occurred by cesarean section at 39 weeks of gestational age. There was a good adaptation to extrauterine life, and risk factors of early-onset sepsis were absent. Weight, length, and head circumference were adequate for gestational age, according to the Fenton growth chart.

On day 1 of life, the physical examination showed dispersed petechiae in the trunk and lower limbs, with no other abnormalities. Laboratory examinations revealed severe neutropenia (ANC 100/μL), mild thrombocytopenia (platelet count 135 000/μL), and positive direct Coombs test, without anemia or hyperbilirubinemia. Infectious diseases were ruled out. In particular, there was no history of maternal infections; the mother's platelet and neutrophil counts were normal; her serological studies for hepatitis B, hepatitis C, HIV, and syphilis were negative; and she was immune to cytomegalovirus, rubella, and toxoplasmosis. Newborn's bacteriological blood cultures were also negative. The newborn always maintained good vitality and showed no other abnormalities despite a transient increase in C-reactive protein [Table 1].
Table 1: Results of laboratory evaluations

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NAN was confirmed by flow cytometry, showing the presence of IgG antibodies on the membrane of the newborn's neutrophils and in the maternal serum. These antibodies were reactive to the paternal neutrophils. The study of the polymorphisms of the genes encoding for HNA revealed the following genotypes: mother: HNA-1a/HNA-3b/HNA-4a/HNA-5ab; father: HNA-1b/HNA-3ab/HNA-4ab/HNA-5ab; and newborn: HNA-1b/HNA-3ab/HNA-4a/HNA-5b. Thus, HNA-1b and/or HNA-3a were identified as potential causes of mother/newborn incompatibility.

During hospitalization, there was a progressive improvement in neutrophil and platelet counts [Table 1], and infectious complications were not observed. The newborn was discharged home at 11 days of life and followed as an outpatient. On day 15, the neutrophil and platelet counts were already normal.

  Discussion Top

Neutropenia is an abnormality frequently identified in neonatal intensive care units.[6] In neonates, it is mostly due to nonimmune causes including maternal hypertension, sepsis, low birth weight, and twin–twin transfusion.[2],[6] NAN is much less frequent than neonatal neutropenia of prematurity.[7] Further evaluation of neonatal neutropenia should be considered when the ANC does not increase within 3–5 days and/or if no other clear underlying cause is present.[2] An immune-mediated etiology involving antineutrophil antibodies should be considered in a well-appearing neonate with persistent neutropenia,[6] as it was in this newborn.

The diagnosis requires testing maternal serum for antineutrophil antibodies against neutrophils from the father, reactive with HNA, and HNA genotyping of both the parents and the neonate.[2],[7] In this case, the possible implicated HNAs were HNA-1b and/or HNA-3a. Currently, 11 HNAs within five different HNA systems are known: four HNA-1 alleles, HNA-2, two HNA-3, two HNA-4 alleles, and two HNA-5 alleles.[8] The HNA-1 system is carried by the Fc-gamma receptor IIIb (FcγRIIIb and CD16) and includes HNA-1a,-1b,-1c, and-1d.[2] The HNA-3 system is located on the choline transporter-like protein 2 and includes the HNA-3a and-3b alleles.[2] Most cases of NAN are caused by antibodies, specific for HNA-1a and HNA-1b.[2] The alleles HNA-3a and-3b, which have an estimated allele frequency in Caucasians of 0.79 and 0.21, respectively, have only rarely been implicated in NAN.[2],[9] However, it is known that HNA-3a-specific antibodies may cause severe, often fatal, transfusion-associated acute lung injury.

According to the literature, NAN may happen in the first pregnancy, suggesting that maternal immunization can occur during the pregnancy or even before.[2] In the case herein described, parents already had a first child who was clinically unaffected. However, the possibility of an undiagnosed NAN cannot be excluded. Despite the high probability of recurrence of NAN in a future pregnancy, given the wide spectrum of severity of neutropenia, the couple was not oriented for genetic counseling. In this case, future neonates should have a complete blood count to assess the ANC and they should be kept under closer surveillance.

As mentioned above, in most cases of NAN, the neonates do not present clinical symptoms or infections. In our case, the unique signal presented was a petechial rash, possibly related to mild thrombocytopenia also present. There are cases describing combined NAN and neonatal alloimmune thrombocytopenia (NAIT) that result from maternal incompatibility for human platelet alloantigens (HPAs) of paternal origin.[10],[11] The clinical presentation of the syndrome varies from mild thrombocytopenia to severe, and the most common manifestation is generalized petechia developing in the first minutes or hours of life in healthy newborn.[10] However, in our case, given the moderate and transient thrombocytopenia, the investigation for these antibodies has not been carried out. Another possible explanation for the coexistence of neutropenia and thrombocytopenia could be the presence of human leukocyte antigen (HLA) antibodies. Both platelets and neutrophils express HLA proteins; although HLA antibodies are very common in pregnant women, occurring in up to one-third of pregnancies, it is rare that these antibodies cause alloimmune thrombocytopenia and neutropenia.[11],[12],[13] However, there are reports of NAN and NAIT caused by HLA antibodies,[11] with and without concomitant HNA and HPA antibodies.[10],[12],[13] It should be noted that thrombocytopenia and neutropenia induced by HLA-antibodies are, always, a diagnosis of exclusion.[11],[12]

The treatment recommended for NAN includes antibiotics, high-dose IVIG, and G-CSF. Although recommended in cases of severe neutropenia, the effectiveness of prophylactic antibiotics is controversial.[2],[6] G-CSF is a physiologic regulator of neutrophil production and increases neutrophil numbers by inducing myeloid proliferation and granulocyte maturation and stimulating the release of neutrophils from the bone marrow.[14] Most infants with NAN and other forms of immune-mediated neutropenia respond to G-CSF at doses of 5–10 mcg/kg/day administered intravenously or subcutaneously, the response being usually obvious within 24–48 h.[6] Since NAN is self-limited, G-CSF treatment is required only for short periods, is well tolerated, and without side effects.[6] High-dose IVIG, usually 400 mg/kg daily for 5 days or 1 g/kg/day for 2 days, has also been used with success in some patients with NAN, usually as second-line treatment.[2] Its primary mechanism of action is through the blockade of the Fc receptors of the reticuloendothelial system, allowing antibody-coated neutrophils to escape phagocytosis by the macrophages; however, IVIG is has multiple activities, including modulation of complement activation and cytokine secretion.[15] Steroids, sometimes used to treat autoimmune neutropenia, were not shown to be effective in NAN and are not recommended.[6] Despite the very low ANC, taking into consideration the general good condition of the newborn, we decided to have expectant management, adopting only measures related to minimizing contacts and universal precautions such as hygienic hand disinfection. It is notable that, despite the severe neutropenia, the newborn had an excellent clinical evolution without infections.

In conclusion, even though NAN is rare, it should be considered in neutropenic neonates, especially in absence of other attributable causes. As documented in this case, laboratory investigation to establish the diagnosis requires detection of antineutrophil alloantibodies and HNA genotyping to identify the implicated antigen, performed by qualified laboratories. Also as occurring in this case, NAN is usually a self-limiting condition that resolves within a few weeks after birth without major complications. In general, there are only mild bacterial infections, and antibiotic treatment is effective. However, fatal outcomes may occur in the most severe cases associated with sepsis. Thus, timely diagnosis, clinical monitoring, and the exclusion of intercurrent infections are essential to prevent severe complications.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.


The authors would like to thank Sónia Fonseca and João Rodrigues (Hematological Diagnosis Unit, Cytometry and Genetics Laboratories, Centro Hospitalar Universitário do Porto) for contributing to laboratory studies.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Curtis BR, Reno C, Aster RH. Neonatal alloimmune neutropenia attributed to maternal immunoglobulin G antibodies against the neutrophil alloantigen HNA-1c (SH): A report of five cases. Transfusion 2005;45:1308-13.  Back to cited text no. 1
Porcelijn L, de Haas M. Neonatal alloimmune neutropenia. Transfus Med Hemother 2018;45:311-6.  Back to cited text no. 2
Ioannidou M, Hatzipantelis E, Tragiannidis A. A case report of neonatal alloimmune neutropenia in a neonate. Hippokratia 2019;23:143.  Back to cited text no. 3
Coates T. Immune Neutropenia. UpToDate; Oct 2020. Available from: https://www.uptodate.com/contents/immune-neutropenia?csi=0849543c-9114-4628-9475-27a6d2c8d7d5&source=contentShare. [Last accessed on 2020 Nov ].  Back to cited text no. 4
Han TH, Chey MJ, Han KS. A case of neonatal alloimmune neutropenia associated with anti-human neutrophil antigen-1a (HNA-1a) antibody. J Korean Med Sci 2006;21:351-4.  Back to cited text no. 5
Maheshwari A. Neutropenia in the newborn. Curr Opin Hematol 2014;21:43-9.  Back to cited text no. 6
Dale DC. How I manage children with neutropenia. Br J Haematol 2017;178:351-63.  Back to cited text no. 7
Flesch BK, Reil A. Molecular genetics of the human neutrophil antigens. Transfus Med Hemother 2018;45:300-9.  Back to cited text no. 8
Lopes LB, Abbas SA, Moritz E, Martins JO, Chiba AK, Langhi DM Jr., et al. Antibodies to human neutrophil antigen HNA-3b implicated in cases of neonatal alloimmune neutropenia. Transfusion 2018;58:1264-70.  Back to cited text no. 9
Taaning E, Jensen L, Varming K. Simultaneous occurrence of foetal and neonatal alloimmune thrombocytopenia and neonatal neutropenia due to maternal neutrophilic autoantibodies: A case study and review of the literature. Acta Paediatr 2012;101:896-9.  Back to cited text no. 10
Marques S, Lucas M, Rodrigues A, Ferreira AR, Carvalhosa G, Neto AS. A Case of Alloimune Thrombocytopenia with Neutropenia: Um Caso de Trombocitopenia Neonatal com Neutropenia. Gaz Med [Internet] 2018;4.  Back to cited text no. 11
Gramatges MM, Fani P, Nadeau K, Pereira S, Jeng MR. Neonatal alloimmune thrombocytopenia and neutropenia associated with maternal human leukocyte antigen antibodies. Pediatr Blood Cancer 2009;53:97-9.  Back to cited text no. 12
Marín L, Torío A, Muro M, Fernandez-Parra R, Minguela A, Bosch V, et al. Alloimmune neonatal neutropenia and thrombocytopenia associated with maternal anti HNA-1a, HPA-3b and HLA antibodies. Pediatr Allergy Immunol 2005;16:279-82.  Back to cited text no. 13
Calhoun DA, Christensen RD. Human developmental biology of granulocyte colony-stimulating factor. Clin Perinatol 2000;27:559-76.  Back to cited text no. 14
Jin F, Balthasar JP. Mechanisms of intravenous immunoglobulin action in immune thrombocytopenic purpura. Hum Immunol 2005;66:403-10.  Back to cited text no. 15


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