DOI: 10.1002/pd.4413
ORIGINAL ARTICLE
Clinical presentation and outcome of 20 fetuses with parvovirus B19 infection complicated by severe anemia and/or fetal hydrops Guillaume Macé1,2*, Marine Sauvan1, Vanina Castaigne1, Marie-Laure Moutard3, Anne Cortey4, Emeline Maisonneuve1, Catherine Garel5, Ferdinand Dhombres1, Jeremy Boujenah1, Agnès Mailloux4 and Bruno Carbonne1,4 1
Unité d’Obstétrique-Maternité, Hôpital Trousseau, Assistance Publique - Hôpitaux de Paris, Université Pierre et Marie Curie, Paris VI, France Service de Gynécologie-Obstétrique, CHU Bocage, Université de Bourgogne, Dijon, France 3 Trousseau Hospital, Pierre et Marie Curie University, Pediatric Neurology, Paris, France 4 Centre National de Référence en Hémobiologie Périnatale, Hôpitaux Universitaires Est-Parisien, Assistance Publique - Hôpitaux de Paris, Paris, France 5 Service de Radiologie Pédiatrique, Hôpital Trousseau, Assistance Publique - Hôpitaux de Paris, Paris, France *Correspondence to: Guillaume Macé. E-mail: [email protected] 2
ABSTRACT Aim The aim of this study was to assess the prognosis of parvovirus B19 infection with severely anemic and/or hydropic fetuses according to initial ultrasound and biological criteria. Material and methods Retrospective study of 20 cases of congenital parvovirus B19-proven infection (positive PCR) complicated by fetal anemia and/or hydrops was examined. Anemia was suspected on an elevated peak systolic velocity of the middle cerebral artery and was confirmed by fetal blood sampling. Results Survival rate was 70% (14/20) overall and 76% (13/17) for fetuses with one or more transfusions. When fetal effusion regressed after the transfusion, all 11 fetuses survived, and neonatal condition was favorable for all. Among the 14 live-born children, there was one neonatal death and one admission to the neonatal care unit with no major complications.
Conclusion Despite active management by transfusion in fetuses with parvovirus B19 infection, mortality remained substantial during the acute phase of anemia and fetal hydrops. Regression of effusion appears to be an important variable for prognosis. Non-anemic forms exist with isolated refractory ascites or pleural effusion. Maternal mirror syndrome appears to reflect the intensity and persistence of the fetal anemia. © 2014 John Wiley & Sons, Ltd.
Funding sources: None Conflicts of interest: None declared
INTRODUCTION Congenital infection by parvovirus B19 is rare and often asymptomatic, but it causes fetal complications in approximately 10% of cases.1–3 In case of maternal infection, there is a 6.3% risk of in utero fetal death (IUFD) and a 3.9% risk of fetal hydrops.2 Vertical transmission of parvovirus B19 infection through the placental blood barrier is estimated around 30% to 50%.4–6 Parvovirus B19 inhibits fetal hematopoiesis by lysis of the erythroid precursors, leading to erythroblastopenia; it may also block myocardiocyte action.4,5,7 Accordingly, fetal complications include anemia, heart failure, and fetal hydrops.5 The diagnosis of fetal anemia is suggested on ultrasound by an elevated peak systolic velocity of the middle cerebral artery (MCA-PSV) on Doppler examination.8–13 In utero transfusion (IUT) is indicated when the MCA-PSV exceeds 1.5 multiples of the median (MoM). Overall survival ranges from 58% to 77%, and the neonatal consequences are variable, but the prognosis for these severe Prenatal Diagnosis 2014, 34, 1023–1030
forms is globally good after birth.14,15 In cases of late diagnosis or extremely severe forms, parvovirus B19 infection can lead to IUFD occurring most often between 20 and 24 weeks of gestation.5 The IUT can lead to progressive regression of the hydrops. In such cases, perinatal mortality is reduced significantly.2,16–18 Multiple IUTs are sometimes necessary to get over erythroblastopenia. This study examines a series of 20 pregnancies with documented parvovirus B19 infections, complicated by severe fetal anemia and/or serous effusion; we also report their course after IUT. We discuss the laboratory and ultrasound factors that are prognostic, as well as the pathophysiologic hypotheses about complete and incomplete (non-anemic or non-hydropic) presentations.
MATERIAL AND METHODS This continuous series includes all cases of congenital parvovirus B19 infections complicated by severe anemia or multiple serous effusions, identified retrospectively and © 2014 John Wiley & Sons, Ltd.
G. Macé et al.
1024
referred from 1 January 2005 to 30 April 2013, to the National Reference Center for Perinatal Hemobiology (CNRHP). The women were referred to the CNRHP when fetal hydrops or effusion was identified by ultrasound, most often associated with an elevated MCA-PSV. The initial ultrasound work-up included a complete morphologic examination searching for a cause of hydrops and measurement of the MCA-PSV, which strongly suggested fetal anemia when exceeding 1.5 MoM. Laboratory testing for potential causes are sought to rule out alloimmunization (indirect antiglobulin test), fetomaternal hemorrhage (Kleihauer–Betke test), and maternal infection by either cytomegalovirus or parvovirus B19. When the fetal MCA-PSV exceeded 1.5 MoM, a fetal blood sample was taken through the umbilical vein under ultrasound guidance without waiting for the results of the maternal laboratory tests. Fetal hemoglobin levels were measured immediately with a hemoglobin analyzer (Hemocue®, Part of the Radiometer Group, Hemocue AB, Angelhem, Sweden), and transfusion of O rhesus D-negative packed red cells was started immediately in case of fetal anemia. The volume of blood to be transfused was determined by charts established in our Reference Center (unpublished data), taking into account the estimated fetal weight, the initial fetal hemoglobin and target fetal hemoglobin level, and the hematocrit of the packed red cells. Fetal hemoglobin was checked by Hemocue® when about half of the calculated volume had been transfused and then by intermittent blood samplings throughout the end of the procedure in order to validate the progression of fetal hemoglobin A complete blood count was also performed on
the sample and at the beginning of the procedure; it included platelet and reticulocyte count, PCR for parvovirus B19 and CMV, and a liver function tests when possible. Monitoring during the first days after IUT relied on daily ultrasound examination in order to identify signs of recurrence of anemia, especially a rise in MCA-PSV. Repeated IUTs could be performed when anemia recurred. Fetal parvovirus infection was diagnosed by PCR on amniotic fluid, fetal blood, or both. The course and outcome of these pregnancies were identified from the patients’ medical records, as well as the clinical, laboratory, and ultrasound data. The quantitative variables are presented as means with their standard deviations.
RESULTS This study included 20 women whose fetuses had confirmed congenital parvovirus B19 infection. These were all singleton pregnancies, diagnosed at a mean gestational age of 23+4 weeks (±14 days) (range: 20 to 30 weeks). Only 3 of the 20 women (15%) reported clinical symptoms of viral infection (fever and myalgia) in early pregnancy. All women but one were referred for fetal hydrops or isolated effusion on ultrasound: 18 during the second trimester, one during the third trimester. One woman was referred for decreased fetal movements at 27 weeks. The ultrasound examination revealed fetal hydrops and an increased MCA-PSV above 1.5 MoM. Figure 1 summarizes the management of the 20 fetuses and their clinical course, whereas Table 1 details their individual clinical, laboratory, and imaging data.
Figure 1 Management and outcome of 20 fetuses with parvovirus B19-induced hydrops and/or anemia
Prenatal Diagnosis 2014, 34, 1023–1030
© 2014 John Wiley & Sons, Ltd.
Prenatal Diagnosis 2014, 34, 1023–1030
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Serous effusion at admission
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ORIGINAL ARTICLE
Clinical presentation and outcome of 20 fetuses with parvovirus B19 infection complicated by severe anemia and/or fetal hydrops Guillaume Macé1,2*, Marine Sauvan1, Vanina Castaigne1, Marie-Laure Moutard3, Anne Cortey4, Emeline Maisonneuve1, Catherine Garel5, Ferdinand Dhombres1, Jeremy Boujenah1, Agnès Mailloux4 and Bruno Carbonne1,4 1
Unité d’Obstétrique-Maternité, Hôpital Trousseau, Assistance Publique - Hôpitaux de Paris, Université Pierre et Marie Curie, Paris VI, France Service de Gynécologie-Obstétrique, CHU Bocage, Université de Bourgogne, Dijon, France 3 Trousseau Hospital, Pierre et Marie Curie University, Pediatric Neurology, Paris, France 4 Centre National de Référence en Hémobiologie Périnatale, Hôpitaux Universitaires Est-Parisien, Assistance Publique - Hôpitaux de Paris, Paris, France 5 Service de Radiologie Pédiatrique, Hôpital Trousseau, Assistance Publique - Hôpitaux de Paris, Paris, France *Correspondence to: Guillaume Macé. E-mail: [email protected] 2
ABSTRACT Aim The aim of this study was to assess the prognosis of parvovirus B19 infection with severely anemic and/or hydropic fetuses according to initial ultrasound and biological criteria. Material and methods Retrospective study of 20 cases of congenital parvovirus B19-proven infection (positive PCR) complicated by fetal anemia and/or hydrops was examined. Anemia was suspected on an elevated peak systolic velocity of the middle cerebral artery and was confirmed by fetal blood sampling. Results Survival rate was 70% (14/20) overall and 76% (13/17) for fetuses with one or more transfusions. When fetal effusion regressed after the transfusion, all 11 fetuses survived, and neonatal condition was favorable for all. Among the 14 live-born children, there was one neonatal death and one admission to the neonatal care unit with no major complications.
Conclusion Despite active management by transfusion in fetuses with parvovirus B19 infection, mortality remained substantial during the acute phase of anemia and fetal hydrops. Regression of effusion appears to be an important variable for prognosis. Non-anemic forms exist with isolated refractory ascites or pleural effusion. Maternal mirror syndrome appears to reflect the intensity and persistence of the fetal anemia. © 2014 John Wiley & Sons, Ltd.
Funding sources: None Conflicts of interest: None declared
INTRODUCTION Congenital infection by parvovirus B19 is rare and often asymptomatic, but it causes fetal complications in approximately 10% of cases.1–3 In case of maternal infection, there is a 6.3% risk of in utero fetal death (IUFD) and a 3.9% risk of fetal hydrops.2 Vertical transmission of parvovirus B19 infection through the placental blood barrier is estimated around 30% to 50%.4–6 Parvovirus B19 inhibits fetal hematopoiesis by lysis of the erythroid precursors, leading to erythroblastopenia; it may also block myocardiocyte action.4,5,7 Accordingly, fetal complications include anemia, heart failure, and fetal hydrops.5 The diagnosis of fetal anemia is suggested on ultrasound by an elevated peak systolic velocity of the middle cerebral artery (MCA-PSV) on Doppler examination.8–13 In utero transfusion (IUT) is indicated when the MCA-PSV exceeds 1.5 multiples of the median (MoM). Overall survival ranges from 58% to 77%, and the neonatal consequences are variable, but the prognosis for these severe Prenatal Diagnosis 2014, 34, 1023–1030
forms is globally good after birth.14,15 In cases of late diagnosis or extremely severe forms, parvovirus B19 infection can lead to IUFD occurring most often between 20 and 24 weeks of gestation.5 The IUT can lead to progressive regression of the hydrops. In such cases, perinatal mortality is reduced significantly.2,16–18 Multiple IUTs are sometimes necessary to get over erythroblastopenia. This study examines a series of 20 pregnancies with documented parvovirus B19 infections, complicated by severe fetal anemia and/or serous effusion; we also report their course after IUT. We discuss the laboratory and ultrasound factors that are prognostic, as well as the pathophysiologic hypotheses about complete and incomplete (non-anemic or non-hydropic) presentations.
MATERIAL AND METHODS This continuous series includes all cases of congenital parvovirus B19 infections complicated by severe anemia or multiple serous effusions, identified retrospectively and © 2014 John Wiley & Sons, Ltd.
G. Macé et al.
1024
referred from 1 January 2005 to 30 April 2013, to the National Reference Center for Perinatal Hemobiology (CNRHP). The women were referred to the CNRHP when fetal hydrops or effusion was identified by ultrasound, most often associated with an elevated MCA-PSV. The initial ultrasound work-up included a complete morphologic examination searching for a cause of hydrops and measurement of the MCA-PSV, which strongly suggested fetal anemia when exceeding 1.5 MoM. Laboratory testing for potential causes are sought to rule out alloimmunization (indirect antiglobulin test), fetomaternal hemorrhage (Kleihauer–Betke test), and maternal infection by either cytomegalovirus or parvovirus B19. When the fetal MCA-PSV exceeded 1.5 MoM, a fetal blood sample was taken through the umbilical vein under ultrasound guidance without waiting for the results of the maternal laboratory tests. Fetal hemoglobin levels were measured immediately with a hemoglobin analyzer (Hemocue®, Part of the Radiometer Group, Hemocue AB, Angelhem, Sweden), and transfusion of O rhesus D-negative packed red cells was started immediately in case of fetal anemia. The volume of blood to be transfused was determined by charts established in our Reference Center (unpublished data), taking into account the estimated fetal weight, the initial fetal hemoglobin and target fetal hemoglobin level, and the hematocrit of the packed red cells. Fetal hemoglobin was checked by Hemocue® when about half of the calculated volume had been transfused and then by intermittent blood samplings throughout the end of the procedure in order to validate the progression of fetal hemoglobin A complete blood count was also performed on
the sample and at the beginning of the procedure; it included platelet and reticulocyte count, PCR for parvovirus B19 and CMV, and a liver function tests when possible. Monitoring during the first days after IUT relied on daily ultrasound examination in order to identify signs of recurrence of anemia, especially a rise in MCA-PSV. Repeated IUTs could be performed when anemia recurred. Fetal parvovirus infection was diagnosed by PCR on amniotic fluid, fetal blood, or both. The course and outcome of these pregnancies were identified from the patients’ medical records, as well as the clinical, laboratory, and ultrasound data. The quantitative variables are presented as means with their standard deviations.
RESULTS This study included 20 women whose fetuses had confirmed congenital parvovirus B19 infection. These were all singleton pregnancies, diagnosed at a mean gestational age of 23+4 weeks (±14 days) (range: 20 to 30 weeks). Only 3 of the 20 women (15%) reported clinical symptoms of viral infection (fever and myalgia) in early pregnancy. All women but one were referred for fetal hydrops or isolated effusion on ultrasound: 18 during the second trimester, one during the third trimester. One woman was referred for decreased fetal movements at 27 weeks. The ultrasound examination revealed fetal hydrops and an increased MCA-PSV above 1.5 MoM. Figure 1 summarizes the management of the 20 fetuses and their clinical course, whereas Table 1 details their individual clinical, laboratory, and imaging data.
Figure 1 Management and outcome of 20 fetuses with parvovirus B19-induced hydrops and/or anemia
Prenatal Diagnosis 2014, 34, 1023–1030
© 2014 John Wiley & Sons, Ltd.
Prenatal Diagnosis 2014, 34, 1023–1030
22
22
23
22
9
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27
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Serous effusion at admission
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