Postnatal IVIG Treatment for Persistent Anemia in Neonate due to Congenital Parvovirus Infection

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Parvovirus B19 is a small non-enveloped single stranded DNA virus that frequently infects humans. Parvovirus B19 can cause erythema infectiosum, also known as fifth disease, characterized by self-limited fever, rash, and arthropathy. The incidence of parvovirus B19 infection in pregnancy is 3.3-3.8% [1]. Approximately 30-50% of pregnant women are non-immune and vertical transmission is common [2]. 

During pregnancy, Parvovirus B19 is cytotoxic to fetal red blood cell precursors. The virus is highly trophic to human bone marrow and replicated in erythroid progenitor cells. [3,4]. Most intrauterine parvovirus infections do not have adverse outcomes; however, in rare cases, transplacental transmission of Parvovirus B19 in the setting of maternal viremia can result in fetal hydrops or death due to severe fetal anemia [4]. Parameters of hydrops fetalis include scalp and skin edema, ascites, pleural effusions, and pericardial effusions.

During pregnancy, a positive parvovirus B19 specific immunoglobulin antibody can be used to diagnose acute or chronic maternal infection. Polymerase chain reaction (PCR) detection of B19 in the amniotic fluid is the method of choice for diagnosis of congenital parvovirus infection [5]. Fetal anemia is suspected on ultrasound examination when middle cerebral artery peak systolic velocity (MCA PSV) Doppler is >1.5 MoM [6]. Percutaneous umbilical cord blood sampling (PUBS) examines blood from the fetal umbilical cord and confirms the diagnosis. In severe cases of fetal anemia, intrauterine red blood cell transfusions may be indicated to prevent fetal death [7].

After delivery, congenital infection may result in persistent neonatal viremia with secondary pure red cell aplasia (PRCA) and chronic anemia. The mainstay of treatment for PRCA in neonates is red cell transfusion(s). In certain patients with persistently high viral loads, intravenous immunoglobulin (IVIG) has been used successfully for treatment of persistent parvovirus induced anemia, but data remains limited in neonates [10-14]. Here, we describe a case of congenital parvovirus infection in a preterm infant complicated by hydrops fetalis that responded to a postnatal treatment of IVIG.


A preterm male neonate was born at 29 weeks and 2 days gestation to a 27 year old gravida 5, para 1 mother. Serologies were negative (rapid plasma reagin non-reactive, HIV antibody screen negative, Hepatitis B surface antigen negative, Group B streptococcal status negative). The prenatal course was complicated by ultrasound findings of polyhydramnios, with an amniotic fluid index (AFI) up to 28.5 cm. Fetal ultrasound at 27 weeks and 2 days gestation showed scalp edema, ascites, pleural and pericardial effusions, skin edema, and elevated middle cerebral arterial Doppler's consistent with fetal hydrops. Fetal echocardiogram revealed a structurally normal heart. Serologic testing showed maternal Parvovirus seroconversion (positive Parovirus B19 immunoglobulin M [IgM] with a previously documented negative Parvovirus B19 immunoglobulin G [IgG]). Maternal Parvovirus polymerase chain reaction (PCR) confirmed positive. The mother had no known sick contacts and no history of febrile illness, rashes, joint pain or other infectious symptoms during pregnancy.

In the setting of the persistent fetal anemia and severe hydrops, the decision was made to perform a PUBs procedure with intrauterine transfusion of packed red blood cells total three times, at 27 weeks and 3 days, 28 weeks and 1 day, and 28 weeks and 3 days gestation. Red blood cell transfusion consisted of leukocyte reduced, irradiated, CMV negative, type O negative blood. Pre-procedure MCA PSV Dopplers for the three procedures were 106 cm/sec, 73.8 cm/sec, and 72 cm/sec with MCA PSV multiples of the median (MoM) averaging 3.0, 1.99 and 1.92, respectively. Pre-transfusion fetal hematocrit levels were 6.8, 15, and 20%. Post-procedure hematocrits increased to >25% with normalization of MCA dopplers in each case. Last Doppler prior to delivery at 29 weeks and 0 days had an MCA PSV of 60 cm/sec (1.58 MoM). Fetal reticulocyte count 2.2%. The mother also received intrauterine transfusions of platelets for thrombocytopenia, with lowest fetal platelet count 48 x106 /L.

The mother returned with preterm premature rupture of membranes in preterm labor and delivered at 29 weeks and 2 days via precipitous vaginal delivery. The first course of Betamethasone was given at 27 weeks gestation and a rescue dose was administered immediately prior to delivery. The neonate was intubated in the delivery room for respiratory depression and low heart rate. Apgars were 4 at 1 minute and 7 at 5 minutes of life. Surfactant was given on day of life 0.

Initial physical exam was significant for generalized edema and infiltrated skin with no palpable hepatosplenomegaly. Initial postnatal blood work showed white blood cell count of 10,200/mm3 , hemoglobin of 10 g/dL, hematocrit of 29.2%, and platelet count of 65 x106 /L. Mother's blood type was A positive and newborn's blood type was O negative, Coombs negative. Postnatal ECHO on day of life 2 showed normal segmental anatomy with qualitatively normal biventricular size and systolic function and estimated pulmonary artery pressures approximately half systemic to systemic; no pericardial effusion.

The neonate received both pack red blood cells and platelet transfusions on day of life 0. A single donor was used for iterative transfusions. Hematocrit level initially improved to 45.3%, but then continued to trend down over the following weeks. Reticulocyte count ranged from 0.9 to 1.7% during first six weeks of life. Subsequent red blood cell transfusions were administered on days of life 18, 32 and 46 for persistent anemia with hematocrit

Given the transfusion dependent anemia and poor reticulocytosis, a transient compromise in erythroblastic differentiation due to the Parvovirus infection was considered. A Parvovirus titer was sent on day of life 41 and confirmed a high Parvovirus B19 viral load of >10,000,000 copies/mL, which exceeded level of count. Decision was made to treat the neonate with one dose of IVIG (dose: 1 gm/kg) on day of life 44 for pure red cell aplasia. Bloodwork within 24 hours after administration showed hemoglobin 8.0 g/dL, hematocrit 23.8%, and reticulocyte count 1.3%. Within one week after administration, hemoglobin and hematocrit increased to 11.1 g/dL and 33.1%, and reticulocyte count increased for the first time to 3.7%. On day of life 67, hemoglobin and hematocrit remained stable at 10.1 g/dL and 31.3%, while the reticulocyte count continued to increase to 4.3%. On day of life 77, lab studies showed hemoglobin 10.6 g/dL, hematocrit 31.8%, and reticulocyte count 3.9% with no subsequent need for transfusions. Serum Parvovirus B19 PCR obtained on day of life 92 showed a significant decrease in viral load to 582,550 negative copies/mL.

After IVIG administration, the neonate clinically improved and remained hemodynamically stable throughout hospital course. Extubation was performed on day of life 2 with full wean off respiratory support to room air on day of life 47. Hospital course was complicated by issues including apnea of prematurity, oral feeding, and weight gain; however, the neonate was safely discharged home on day of life 74 (at corrected age 39 weeks and 5 days gestation). Patient was followed outpatient up to 5 months of age with no subsequent evidence of anemia


Parvovirus B19 infection during pregnancy is associated with adverse fetal outcomes, including non-immune fetal hydrops, fetal myocarditis, and fetal death. Fetal anemia due to Parvovirus infection in combination with the shorter half-life of fetal red blood cells can lead to the severe anemia, hypoxia, and fetal hydrops associated with high output cardiac failure. Other proposed mechanisms for fetal hydrops in the setting of Parvovirus B19 include fetal viral myocarditis that leads to cardiac failure and direct damage to hepatocytes that results in hepatic  dysfunction [8]. While Parvovirus has a stronger affinity for hematopoietic system cells, including erythroid progenitor cells, it can also affect leukocyte and megakaryocyte cell lines. Thrombocytopenia is reported in up to 97% of hydropic fetuses [9]. The risk of anemia and fetal hydrops appears to be greater when women are infected with Parvovirus B19 in the first half of pregnancy.

The treatment for Parvovirus related hydrops fetalis and chronic neonatal anemia depends on the gestational age of the infant, other associated conditions, and severity of the illness. Many hydropic infants require mechanical ventilation due to pulmonary hypoplasia or pulmonary edema, abdominal paracentesis for ascites and thoracentesis for pleural effusions. The mainstay of treatment for chronic anemia secondary to PRCA is red blood cell transfusions. However, neonates are especially susceptible to the effects of Parvovirus B19 and their immature immune systems make it difficult to control the infection. In severely persistent cases, alternative therapies, such as IVIG, can be considered.

IVIG is an immunomodulator that was initially used to treat primary immunodeficiencies, but is now being used as primary or adjuvant treatment for various autoimmune and inflammatory diseases, including acute infection. At this time, data about administration of IVIG for persistent Parvovirus B19 infections is limited to case reports. IVIG administration in-utero to a mother at 24 weeks gestation with Parvovirus B19 induced preeclampsia and fetal hydrops showed favorable maternal and fetal outcomes, with normalization of maternal blood pressures and normal infant development [10]. Postnatal IVIG was also showed to improve congenital Parvovirus valvular myocarditis [11]. Reports of patients with PRCA due to Parvovirus B19 infection treated with IVIG show variable outcomes. Postnatal IVIG treatment of PRCA due to Parvovirus B19 infection in preterm dizygotic twins born at 29 weeks 5 days gestation effectively reduced viral remission and normalized erythropoiesis [12]. Postnatal IVIG was also shown to decrease Parvovirus B19 viral load in preterm infant born at 26 weeks and 6 days gestation with fetal hydrops and chronic post-natal anemia when given at age 3 months [13]. In another case report, IVIG resulted in a marked reduction in viral load and stabilization of hemoglobin level in a patient with persistently high Parvovirus B19 viremia when given at 5 months of age [14]. The mechanism of its action of IVIG in the setting of Parvovirus B19 remains unclear. A possible explanation for successful treatment is that IVIG preparations contain specific neutralizing antibodies, leading to a reduction of the viral load [15].

Based on the persistent, transfusion-dependent Parvovirus B19 induced anemia in our patient, we elected to give IVIG in an attempt to reduce viral load and decrease the need for red blood cell transfusions. Following treatment, we noted a significant decrease in viral burden and stabilization of the hemoglobin level over the following 4-6 weeks with no adverse reactions. This successfully decreased the need for frequent red blood cell transfusions throughout the remainder of his inpatient hospitalization. No additional red blood cell transfusions were required in outpatient follow-up to date.

Successful cases of postnatal IVIG administration to decrease Parvovirus B19 viral load and aid in treatment of Parvovirus B19 induced neonatal anemia and red cell aplasia have been reported in case series. We present another favorable neonatal response to IVIG in the setting of congenital Parvovirus B19 viremia, but this form of treatment is still experimental. Strong recommendations for use of IVIG in neonatal Parvovirus B19 infections cannot be made at this time. Future studies will be needed to determine possible mechanisms of action as well as long term effects.


1. Gratacos, E., et al. The incidence of human parvovirus B19 infection during pregnancy and its impact on perinatal outcome. J Infect Dis 1995; 171(5):1360-1363.

2. Lamont, R. F., et al. Parvovirus B19 infection in human pregnancy. BJOG 2011; 118(2): 175-186.

3. Brown, K. E., et al. Erythrocyte P antigen: cellular receptor for B19 parvovirus. Science 1993; 262(5130):114-117.

4. Brown, K. E. and N. S. Young. Parvovirus B19 infection and hematopoiesis. Blood Rev 1995; 9(3): 176-182.

5. Torok, T. J., et al. Prenatal diagnosis of intrauterine infection with parvovirus B19 by the polymerase chain reaction technique. Clin Infect Dis 1992; 14(1): 149-155.

6. Mari, G., et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 2000; 342(1): 9-14.

7. Society for Maternal-Fetal Medicine. Electronic address, p. s. o., et al. Society for Maternal-Fetal Medicine (SMFM) Clinical Guideline #8: the fetus at risk for anemia--diagnosis and management. Am J Obstet Gynecol 2015; 21(6)2: 697-710.

8. Hichijo, A. and M. Morine . A case of fetal parvovirus b19 myocarditis that caused terminal heart failure. Case Rep Obstet Gynecol 2014: 463571.

9. Crane, J., et al. Parvovirus B19 infection in pregnancy. J Obstet Gynaecol Can 2014; 36(12): 1107-1116.

10. Rugolotto, S., et al. Intrauterine anemia due to parvovirus B19: successful treatment with intravenous immunoglobulins. Haematologica 1999; 84(7): 668-669.

11. Kurland, Y., et al. Congenital Parvovirus Myocarditis treated with IVIG. Pediatrics 2018; 142: 185-185.

12. Lejeune, A., et al. Persistent pure red cell aplasia in dizygotic twins with persistent congenital parvovirus B19 infection-remission following high dose intravenous immunoglobulin. Eur J Pediatr 2014; 173(12): 1723-1726.

13. Nadimpalli, S. S., et al. Congenital Parvovirus B19 Infection: Persistent Viremia and Red Blood Cell Aplasia. Open Forum Infect Dis 2015; 2(2): ofv049.

14. Hudson, A. C., et al. Congenital human parvovirus b19 infection with persistent viremia. Clin Pediatr (Phila) 2015; 54(5): 409-413.

15. Sturm, I., et al. Chronic parvovirus B19 infection-associated pure red cell anaemia in a kidney transplant recipient. Nephrol Dial Transplant 1996; 11(7): 1367-1370.

Icahn School of Medicine at Mount Sinai Hospital
Icahn School of Medicine at Mount Sinai Hospital

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