Asian Journal of Transfusion Science
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Serial intrauterine transfusion for severe fetal anemia due to anti-M alloimmunization

1 Indonesia National Center for Maternal and Children Health, Harapan Kita Mother and Children Hospital, Jakarta, Indonesia
2 Department of Obstetrics and Gynecology, Faculty of Medicine Padjajaran University, Hasan Sadikin General Hospital, Bandung, Indonesia

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Date of Submission10-Jun-2022
Date of Decision18-Jul-2022
Date of Acceptance31-Jul-2022
Date of Web Publication26-Sep-2022


Anti-M antibody is one of the causes of severe fetal anemia and intrauterine death despite its relatively low frequency. A G3P2 26-year-old pregnant woman referred to our hospital at 29 weeks gestational age (WGA) with fetal hydrops. Her second pregnancy results in intrauterine fetal death at 35 WGA due to fetal hydrops. From ultrasound exam, we found singleton live fetus with ascites, cardiomegaly, and pericardial effusion. The peak systolic velocity in the fetal middle cerebral artery (PSV-MCA) was 1.44 multiples of the median corresponding to fetal anemia. The patient's blood group was B RhD+M− N+. A reactive IgG anti-M antibody was detected at 37°C. Fetal hemoglobin (Hb) from the first cordocentesis was 2.2 g/dl and we perform multiple intrauterine transfusions and cesarean section at 34 WGA. The postdelivery Hb level was 10.2 g/dl and infant need three times packed red blood cell transfusions after delivery.

Keywords: Anti-M alloimmunization, fetal anemia, hydrops fetalis, intrauterine transfusion

How to cite this URL:
Kapnosa Hasani RD, Abdurazak G, Pribadi A. Serial intrauterine transfusion for severe fetal anemia due to anti-M alloimmunization. Asian J Transfus Sci [Epub ahead of print] [cited 2023 Mar 24]. Available from:

   Introduction Top

Incompatibility between maternal and fetal red blood cell (RBC) antigens can cause fetal hemolytic disease. The most frequent cause of red-cell alloimmunization is RhD negativity, but anti-M alloimmunization can cause severe fetal hemolytic disease, especially in the Asian population.[1],[2] As one of the most populated countries in Asia, there have been no reports of cases of fetal anemia due to anti-M in Indonesia. This case report describes a woman with a history of normal first pregnancy, and intrauterine fetal death due to hydrops fetalis in the second pregnancy. During this third pregnancy, severe fetal anemia due to anti-M alloimmunization was diagnosed and treated by serial intrauterine transfusions.

   Case Report Top

A 26-year-old woman, 29 weeks pregnant with weeks' gestational age (WGA), has an uncomplicated first pregnancy and intrauterine fetal death at 35 weeks of age due to fetal hydrops in the second pregnancy. From ultrasound exam, we found singleton live fetus with ascites, cardiomegaly, and pericardial effusion. The peak systolic velocity in the fetal middle cerebral artery (PSV-MCA) 1.44 multiple of median (MoM) correspond to fetal anemia. The patient's and husband's regular blood group was B Rhesus +. We plan to perform cordocentesis followed by intrauterine transfusion with packed red blood cell (PRC) type O blood and RhD-.

However, all donor red cell units were incompatible with the indirect antiglobulin test (IAT) suggesting irregular antibody was present at maternal serum. A direct antiglobulin test was performed and found negative along with negative autocontrol. Antibody screening was done using IAT with three cell panels gave a differential of anti-D, anti-k, anti-Fya, anti-M, and anti-s [Table 1]. Specific antibody was identified using 10-cell panels as anti-M. The patient's serum showed 4+ reaction with M+ N+ and M+ N− cells but negative with M− N+ cells in LISS/Coombs cards at 37°C [Table 2]. Positive reaction was found in serum treated with dithiothreitol, suggesting the presence of IgG.
Table 1: Antibody screening

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Table 2: Antibody identification

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Fetal hemoglobin (Hb) from first cordocentesis was 2.2 gr/dl and we perform weekly serial intrauterine transfusion [Table 3] with PRC type O blood, RhD-, M−, and N+. With ultrasound guide free-hand technique, blood was transfused through the umbilical vein and peritoneal cavity cord [Figure 1]. The baby was born by cesarean section at 34 WGA with a weight of 1840 g. The baby had respiratory distress due to transient tachypnea of the newborn and requires assisted ventilation for 2 days. We found low Hb (10.2 g/dl) and low reticulocyte (2.6%).
Table 3: Fetal intrauterine transfusion timeline

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Figure 1: Fetal intrauterine transfusion route: (a) umbilical vein and (b) peritoneal cavity

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A postnatal PRC transfusion was performed, and the baby was safely discharged 32 days after delivery with an Hb level of 12.1 g/dl. During the follow-up, the infant had two episodes of decreased Hb level that required transfusion on day 43 (Hb 8.7 g/dl) and day 70 (Hb 9 g/dl). The infant has consistent normal growth until 6 months of follow-up.

   Discussion Top

Universal antenatal screening for RhD-negative pregnancies and the use of RhD immunoglobulin have significantly reduced the incidence of severe hemolytic disease in the fetus and newborn (HDFN). However, non-RhD antigens still contribute to perinatal morbidity and mortality.[2] The MN blood group was a blood group with two antigens M and N whose production is determined by a gene in chromosome 4.[3],[4] These antigens are fully developed in fetal can be detected as early as 9 weeks gestation.[2] The patient with blood group M− N+ and husband with blood group M+ N− will have offspring with 100% blood group M+ N+ which can potentially react with the maternal anti-M antibody.

In most conditions, the anti-M antibody is primarily an IgM that is considered clinically insignificant because it cannot cross the placenta and reacts optimally at 4°C. In some conditions as in our case, the anti-M subclass was IgG and can react optimally at body temperature and cause varying degrees of hemolysis in the fetus.[2],[5] Data from Western countries reported around 10%–14% of pregnant women have the anti-M antibody, but cases of clinically significant HDFN were extremely low.[5],[6] However, there have been sporadic case reports of severe HDFN of anti-M alloimmunization, mainly in Asia. It suggests that racial and genetic factors may play a role.[2],[7],[8] To our knowledge, this is the first reported case of serial intrauterine transfusion for severe fetal anemia and hydrops fetalis due to anti-M alloimmunization in Indonesia.

Doppler ultrasound measurements of PSV-MCA are highly reliable predictors of fetal anemia secondary to red cell alloimmunization.[2],[8] Even though patient's PSV-MCA was only slightly below threshold (1.44 MoM) and corresponds to mild anemia, we still suspect severe fetal anemia due to the current fetal hydrops status and previous pregnancy history. Fetal blood sampling from cordocentesis confirms our suspicion with Hb result of only 2.2 g/dl. In this case, we decided to perform weekly evaluation and continue with cordocentesis and intrauterine transfusion.

There were a few reported cases of successful management of severe fetal anemia due to anti -M alloimmunization with multiple intrauterine transfusions.[1],[2],[9] Fetal transfusion access sites include the umbilical vein and peritoneal cavity and can be performed multiple times up to eight times.[1],[10] Intraperitoneal route provides indirect access to fetal circulation. The umbilical vein route appears to be more effective and rapid but carries a higher risk of complication than the intraperitoneal route. Some author uses a combined approach (intraumbilical vein followed by intraperitoneal cavity at the same procedure) as it provides a more stable fetal hematocrit between procedures.[10] In in vivo survival study, M-positive RBCs were completely cleared from the maternal circulation within 4 h, whereas M-negative RBCs had normal half-time survival of 29 days.[11] Patient with reactive anti-M antibody should be transfused with RBC with negative antigens to prevent hemolysis and prolong the life of RBC and potentially reduce the number of needed transfusions.

In this case, the infant had low reticulocyte and recurrent drop in Hb level until 70 days after delivery. This finding is consistent with data from several reports that found that 55% of HDFN due to anti-M will develop prolonged anemia in newborns that persisted for up to 70 days after birth.[7],[12] Anti-M antibodies can directly suppress M-positive erythroid precursor cell proliferation in the fetus and cause late-onset postpartum anemia.[5] Infants with maternal anti-M may need closer monitoring regardless of initial Hb.[7]

Declaration of patient consent

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

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Li S, Mo C, Huang L, Shi X, Luo G, Ji Y, et al. Hemolytic disease of the fetus and newborn due to alloanti-M: Three Chinese case reports and a review of the literature. Transfusion 2019;59:385-95.  Back to cited text no. 1
Li L, Huang L, Luo G, Luo Y, Fang Q. Prenatal treatment of severe fetal hemolytic disease due to anti-M alloimmunization by serial intrauterine transfusions. Taiwan J Obstet Gynecol 2017;56:379-81.  Back to cited text no. 2
Seshayyan S. Codominance (Features, Significance and Clinical Implications). In: Seshayyan S, editor. Inderbir Singh's Text Book of Anatomy. Vol. 34. New Delhi: Jaypee Brothers Medical Publishers; 2016. p. 481-3.  Back to cited text no. 3
Sharma D, Murki A, Murki S, Pratap T. Anti-M antibodies as a cause of intrauterine fetal death and neonatal hyperbilirubinaemia. BMJ Case Rep 2014;2014:bcr2014203534.  Back to cited text no. 4
Ohto H, Denomme GA, Ito S, Ishida A, Nollet KE, Yasuda H. Three non-classical mechanisms for anemic disease of the fetus and newborn, based on maternal anti-Kell, anti-Ge3, anti-M, and anti-Jra cases. Transfus Apher Sci 2020;59:102949.  Back to cited text no. 5
Stetson B, Scrape S, Markham KB. Anti-M alloimmunization: Management and outcome at a single institution. AJP Rep 2017;7:e205-10.  Back to cited text no. 6
Yasuda H, Ohto H, Nollet KE, Kawabata K, Saito S, Yagi Y, et al. Hemolytic disease of the fetus and newborn with late-onset anemia due to anti-M: A case report and review of the Japanese literature. Transfus Med Rev 2014;28:1-6.  Back to cited text no. 7
Yu M, Graham K, Pasalic L, Alahakoon TI. Recurrent fetal hydrops with maternal M alloimmunisation: Not a benign condition. BMJ Case Rep 2019;12:e230552.  Back to cited text no. 8
Seo MW, Won HS, Kim SK, Shim JY, Kwon SW, Lee PR, et al. Successful treatment of fetal erythroblastosis due to anti-M alloimmunization with fetal intravascular transfusion. Prenat Diagn 2007;27:385-7.  Back to cited text no. 9
Moise K. Intrauterine Fetal Transfusion of Red Cells. UpToDate. Available from: [Last accessed on 2022 Mar 01].  Back to cited text no. 10
Wikman A, Edner A, Gryfelt G, Jonsson B, Henter JI. Fetal hemolytic anemia and intrauterine death caused by anti-M immunization. Transfusion 2007;47:911-7.  Back to cited text no. 11
Arora S, Doda V, Maria A, Kotwal U, Goyal S. Maternal anti-M induced hemolytic disease of newborn followed by prolonged anemia in newborn twins. Asian J Transfus Sci 2015;9:98-101.  Back to cited text no. 12
[PUBMED]  [Full text]  

Correspondence Address:
Rachmat Dediat Kapnosa Hasani,
Indonesia National Center for Maternal and Children, Harapan Kita Mother and Children Hospital, Jakarta
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ajts.ajts_71_22


  [Figure 1]

  [Table 1], [Table 2], [Table 3]


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