Intravenous immunoglobulin in the management of a rare cause of hemolytic disease of the newborn: Anti-SARA antibodies

Abstract

Hemolytic disease of newborn (HDN) is a condition that develops in a fetus, when the IgG molecules produced by the mother pass through the placenta and attack the fetal red blood cells. HDN can occur due to Rh and ABO incompatibilities between the mother and the fetus as well as due to other allo-immune antibodies belonging to Kell (K and k), Duffy (Fya), Kidd (Jka and Jkb), and MNS (M, N, S, and s) systems. Role of intravenous immunoglobulin in management of HDN is not clear.

SARA red blood cell antigen, first discovered in 1990 is a low frequency antigen. We report, a multiparous female whose pregnancy was complicated by HDN due to anti-SARA antibodies requiring both exchange transfusion and intravenous immunoglobulin. The response was sustained after intravenous immunoglobulin (IVIG) rather than after exchange transfusion.

Keywords

Hemolytic disease of newborn intravenous immunoglobulin RBC antigens

1 Introduction

Red blood cell (RBC) antigens are classified either as blood group systems (eg. ABO, Rh, Kell, Duffy) or as collections of antigens. RBC antigens that do not fit into either groups are sorted into two series based on their frequency in general population: 700 series or 901 series. Low frequency antigens (LFAs) that demonstrate inheritance over at-least two generations with incidence of <1% in a cosmopolitan population but lack evidence of association to any blood group system are designated to be part of 700 series by the International Society for Blood Transfusion [1]. RBC antigens that are common (frequency >90%) are placed in the 901 series. In 1990, an Australian patient’s serum was found to react with cells on an antibody identification panel. Testing including immunoblotting and restriction fragment length polymorphisms was done to exclude all published LFAs. Consequently, the new LFA was named SARA [2].

In 2011, first case of hemolytic disease of newborn (HDN) due to anti-SARA antibodies requiring double volume exchange transfusion (ET) was reported in a Canadian family [3]. We report a unique case of severe HDN due to SARA antibodies in a sibling (born after 6 years) of the patient reported earlier. This infant required both ET and intravenous immunoglobulin (IVIG). The response was sustained after IVIG rather than after ET.

2 Case report

A multiparous female (gravida 10, spontaneous abortions 3) had 6 previous vaginal term deliveries with the same partner (Fig. 1). Of these, 5 were uncomplicated with healthy children. While pregnant in 2008, she delivered a baby boy at 37 weeks who required exchange transfusion due to severe hemolytic anaemia. Work up showed anti-SARA antibodies in the maternal plasma. At that time, it was noted that she had a motor vehicle accident (MVA) at 24–26 weeks gestation.

Fig.1

Pedigree chart. Affected neonates are indicated by shading. Proband is indicated by an arrow.

In the current singleton pregnancy, maternal serology was protective and antibody screen was negative. Ultrasound (US) at 19 weeks gestational age showed middle cerebral artery peak systolic velocity (MCA PSV) of 23.7 cm/sec which was 1 MoM (within normal limits). Antenatal USs were done 2 weekly and showed normal biophysical profiles, MCA PSV suggestive of low risk of anemia and no hydropic changes.

Due to fetal heart rate abnormalities, an emergency C-section was done and a late preterm (34+6 weeks) baby boy weighing 2790 g was born. Apgar scores were 4(1 min) and 7(5 min). He was pale, jaundiced but hemodynamically stable. He required respiratory support (CPAP) at birth which was quickly weaned off. Cord blood testing revealed haemoglobin of 54 g/L (normal- 145–225 g/L), hematocrit of 0.16 L/L (normal- 0.45–0.67 L/L), reticulocyte count 10.3% (normal- 2.0–6.0%) and bilirubin of 181 umol/L (10.5 mg/dl) (exchange level-200 umol/L). DAT (direct anti-globulin test) was positive. Mother was A positive and the infant A negative. Peripheral smear showed spherocytosis, mild polychromasia and nucleated RBCs (96/100 white blood cells), findings consistent with HDN. Central umbilical lines were inserted and intensive phototherapy was started.

Bilirubin at 5 hours age was 252 umol/L (15 mg/dl) (exchange level-220 umol/L) with normal electrolytes. A double volume ET was done. Bilirubin and reticulocyte count decreased to 190 umol/L (11 mg/dl) and 0.8% respectively. Hematocrit improved to 0.48 L/L.

Repeat bilirubin 2 hours later was 257 umol/L (15.1 mg/dl) (exchange level-240 umol/L). Hence one dose of IVIG (1 gram/kg) was given. After IVIG, bilirubin stayed between 150–180 umol/L (9-10 mg/dl) for next 72 hours. Hematocrit and reticulocyte count monitored 6–8 hourly were stable. Blood cultures were negative. The trend of bilirubin and hematocrit is shown in the Fig. 2.

Fig.2

Bilirubin and hematocrit trend over first 120 hours of life.

Highest bilirubin was 290 umol/L (17 mg/dl) on day 12 of life with a phototherapy (PT) level of 300 umol/L. Bilirubin on discharge at 2 weeks of age was 208 umol/L (12 mg/dl).

Follow up hearing screen was normal.

3 Discussion

SARA antigen is a rare cause of HDN detected thus far in only 2 families worldwide [4].

Genetic basis of SARA was investigated by performing whole exome sequencing and bioinformatics analysis on SARA positive members of the Australian and Canadian families. This proved that SARA antigen was encoded by single nucleotide variant on GYPA and SARA has been reassigned to the MNS blood group system raising the possibility of typing when clinically indicated [4]. MNS antigens are present early in development and strong IgG antibodies to variety of MNS antigens have been implicated in HDN.

There was a gap of 6 years between the two pregnancies affected by HDN in this mother. ABO and Rh incompatibility were ruled out. Despite exposure to anti-SARA antibodies in a SARA antigen positive fetus throughout pregnancy, there were no features of hydrops fetalis. In our patient, antenatal MCA PSV done at 2 weekly intervals suggested low risk of hemolysis. The graph (Fig. 3) shows the increase in MCA PSVs noted during pregnancy, which as expected increased with increasing gestational age. The Multiples of Median (MoM) ranged from 0.95 to 1.3. As per the Mari [5] nomogram, these MoM are found in fetuses with mild to moderate hemolysis and do not meet the criteria for either delivery or intrauterine transfusion. However, post-natally these infants may need exchange transfusion. This was demonstrated in the study by Simetka O et al. [6], where 9 out of 9 infants who antenatally had MCA PSV MoMs in the moderate range needed exchange transfusion after birth. The study concluded that the need for postnatal exchange transfusion can be predicted by the rate of increase in the MCA PSV. Detti et al. [7] cautioned that in a fetus at risk for anemia, MCA PSV below the cut-off of 1.5 MoM should not reassure the clinician about the need for ET or other treatment after birth.

Fig.3

Antenatal fetal MCA PSVs.

Also there was a 10 day gap between the last Doppler and the delivery of our baby. Hence it is possible that the hemolytic process started late in the third trimester of pregnancy and was severe enough by the time of birth to need both ET and IVIG. Though the response was sustained after IVIG rather than after ET, it is possible that both ET and IVIG contributed to the resolution of HDN.

HDN due to anti-SARA antibodies affected only 2 out of 10 pregnancies in our case. In 2008 while pregnant, the mother had a MVA that may have resulted in trans-placental hemorrhage and maternal allo-immunization. The mother’s plasma was tested extensively and found to be strongly reactive against SARA positive cells and father’s RBCs but nonreactive for numerous other LFAs. The father’s RBCs were confirmed to be SARA positive, though zygosity is unknown and the mother was SARA negative [3].

IVIG associated with PT has been shown to reduce the need for ET and the duration of PT in newborns with hyperbilirubinemia due to ABO and Rh incompatibilities [8, 9]. However, in a recent systematic review [10], efficacy of IVIG was not conclusive in both Rh and ABO disease with studies of poor quality indicating benefit and studies with low risk of bias suggesting no benefit. There are no reviews of use of IVIG in rare causes of HDN. This could provide basis for future research.

In conclusion, in HDN of unknown etiology, when mother’s antibody screen is negative and infant’s DAT is positive, one should test mother’s serum against father’s and neonate’s RBC to rule out antibodies to LFAs as a rare but potential cause of HDN.

Also there is limited data on use of IVIG in HDN due to LFAs. There was a good response in our case thus enabling to avoid a second ET. However, use of IVIG in HDN due to LFAs needs more multicentre, well powered trials before it is made standard of care.

Conflicts of interest

None

Funding

None

References

Daniels

, Fletcher

, Garratty

, et al. Blood group terminology 2004: From the International Society of Blood Transfusion committee on terminology for red cell surface antigens. Vox Sang 2004;87(4):304–16.

Stern

, Hawksworth

, Watt

, Ford

. A new low-frequency red cell antigen, ‘SARAH’. Vox San 1994;67(1):64–7.

Towns

, Hannon

, Hendry

, Barnes

, Goldman

. Hemolytic disease of the fetus and newborn caused by an antibody to a low-prevalence antigen, anti-SARA. Transfusion 2011;51(9):1977–9.

McBean

, Hyland

, Hendry

, Shabani-Rad

, Flower

. SARA: A “new” low-frequency MNS antigen (MNS47) provides further evidence of the extreme diversity of the MNS blood group system. Transfusion 2015;55(6 Pt 2):1451–6.

Mari

, Deter

, Carpenter

, et al. Noninvasive diagnosis by Doppler Ultrasonography of Fetal Anemia Due to Maternal Red-Cell Alloimmunization. N Engl J Med 2000;342(1):9–14.

Simetka

, Petros

, Lubusky

, et al. Changes in middle cerebral artery velocimetry of fetuses diagnosed postnatally with mild or moderate hemolytic disease. Acta Obstet Gynecol Scand 2014;93(10):1059–64.

Detti

, Mari

, Akiyama

, et al. Longitudinal assessment of the middle cerebral artery peak systolic velocity in healthy fetuses and in fetuses at risk for anemia. Am J Obstet Gynecol 2002;187(4):937–9.

Cortey

, Elzaabi

, Waegemans

, Roch

, Aujard

. Efficacy and safety of intravenous immunoglobulins in the management of neonatal hyperbilirubinemia due to ABO incompatibility: A meta-analysis. Arch Pediatr 2014;21(9):976–83.

, Wang

, Chen

. Meta analysis of the effect of immunoglobulin infusion on neonatal isoimmune hemolytic disease caused by blood group incompatibility. Zhonghua Er ke Za zhi 2010;48(9):656–60.

10.

Louis

, More

, Oberoi

, Shah

. Intravenous immunoglobulin in isoimmune haemolytic disease of newborn: An updated systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed 2014;99(4):F325–31.