Discussion
We describe the clinical course of three neonates born to mothers with history of SARS-CoV-2 infection during pregnancy, who developed intravascular hemolysis while having other concurrent illnesses. Two cases had a reactive anti-SARS-CoV-2 antibodies test. Case 1 had two negative nasopharyngeal swabs for SARS-CoV-2 PCR; cases 2 and 3 were not tested given the negative maternal tests at the delivery. Vertical transmission of SARS-CoV-2, although rare, has been reported, but our cases did not meet the criteria for congenital infection.1 However, there have been reports of newborns born to SARS-CoV-2 positive mother who presented with thrombocytopenia, refractory shock, and multiorgan failure.2 Another study reported NEC in a preterm infant born to a SARS-CoV-2 positive mother. 3
All our cases developed hemolytic anemia early in their course, and it was associated with conditions that predispose to hemolysis such as NEC, G6PD deficiency, and DIC.
Our first case had NEC, a complication of prematurity with an incidence of 5-10% and with mortality rates as high as 30%. 45 Anemia is well described in NEC and is multi-factorial due to bleeding, iatrogenic losses, thrombotic microangiopathy, or activation of the Thomsen-Friedenrich cryptantigen on the RBC. As many as 30 % of newborns with NEC could have TCA activation. 6 Surface TCA is an antigen concealed by a layer of N-acetylneuraminic acid. 8 When TCA is exposed may interact with immunoglobulin M (IgM) anti - T antibodies present in plasma.7 When RBCs are destroyed, hemoglobin is released in plasma and couples irreversibly with haptoglobin. This complex is cleared from circulation by monocytes and macrophages. Low levels of haptoglobin, as in cases 2 and 3, are useful to support the hemolytic etiology, but it is important to note that solely low haptoglobin levels in newborns may not be useful for diagnosis of hemolysis. 8 In case 1, there was a strong clinical suspicion that TCA activation was responsible for the hemolytic process based on positive minor crossmatch. The patient received washed RBC and platelets, PCC, and fibrinogen concentrate with subsequent improvement in hemolysis. Case 3 had decreased level of G6PD. G6PD deficiency is mostly asymptomatic unless there is exposure to oxidative stress, caused by infections, or medications, followed by hemolysis.8 There are reports of a possible association of SARS-CoV2 infection with hemolysis in adults with G6PD deficiency. 9 10
All cases had elevated free plasma hemoglobin, elevated reticulocyte count, schistocytes on peripheral smear, but the direct antiglobulin test (DAT) was negative. 5-10 % of hemolytic anemias may have negative antibody testing on routine testing, 12 due to the presence of a different type of antibody (IgM), small number of RBCs bound to IgG molecules or low-affinity autoantibodies. Additionally, during SARS-CoV-2 infection, hemolytic anemia may be DAT negative, and traditional hemolytic markers may be unreliable.11 As seen in our cases, high plasma hemoglobin levels can be highly pathogenic through direct endothelial damage, lipid peroxidation, or activation of various inflammatory pathways. 1121
None of the previous reports involving newborns born to SARS-CoV-2 positive mothers describe hemolytic anemia, but there are reports of autoimmune hemolytic anemia in adults with SARS-CoV-2 infection, presumably caused by the cytokine storm or through molecular mimicry.14–17 Most of the reported cases of SARS-CoV-2 infection associated with hemolytic anemia had an underlying condition predisposing to hemolysis such as spherocytosis, G-6-PD deficiency, or malignancy 18 similar to our cases.
Our cases highlight the need for a prospective study to identify if the incidence of hemolysis in neonates born to mothers with active or resolved SARS-CoV-2 infection during pregnancy is indeed increased. While a direct causal relationship between intrauterine exposure to SARS-CoV-2 infection or antibodies and hemolysis cannot be definitively proven, based on the clinical presentation, we speculate that infants with conditions known to cause hemolysis are at increased risk of developing a more severe form of hemolytic anemia. If intravascular hemolysis and coagulopathy are present, until further information is available, using washed blood products that are less likely to exacerbate the hemolytic process, irradiated RBC, and PCC might be a consideration.