144 Case Report
Non-immune Hydrops fetalis due to Parvovirus B19 Infection in 2 Extremely Preterm Infants: Perinatal Management and Long-term Neurodevelopmental Outcome Nicht-immuner Hydrops fetalis in Folge Parvovirus B19 Infektion bei 2 extrem frühgeborenen Kindern: Perinatales Management und Langzeit-Outcome Authors
S. Welcker1, M. Heckmann2
Affiliations
1
Key words ▶ Hydrops fetalis ● ▶ parvovirus B19 ● ▶ preterm infants ●
Abstract
Zusammenfassung
Parvovirus B19 (B19V) infection during pregnancy can lead to fetal damage and even fetal loss. In some cases a severe fetal anemia with hydrops fetalis occurs. An intrauterine red blood cell transfusion can reduce the mortality rate. Neuro developmental outcome after fetal B19V infection is affected by fetal anemia and presumably direct infection of the CNS. There are only a few studies on long-term neurodevelopmental outcome after B19V infection induced hydrops fetalis. There are hardly any long-term data especially in preterm infants. We report on the long-term outcomes of 2 extremely preterm children after non-immune hydrops fetalis due to intrauterine B19V Infection.
Eine Parvovirus B19 (B19V) Infektion in der Schwangerschaft kann eine Schädigung des Feten und sogar eine Fehlgeburt zur Folge haben. In einigen Fällen tritt eine schwere fetale Anämie mit Hydrops fetalis auf, dessen Mortalität durch eine intrauterine Bluttransfusion gesenkt werden kann. Das neurologische Outcome wird nicht nur durch das Auftreten eines Hydrops fetalis beeinflusst sondern vermutlich auch durch direkte Infektion des ZNS. Über das Langzeit-Outcome nach B19V-Infektion induzierten Hydrops fetalis gibt es nur wenige Studien. Besonders bei Frühgeborenen liegen kaum Langzeitdaten vor. Wir berichten nun über das Langzeit-Outcome zweierextrem frühgeborener Kinder nach nichtimmunem Hydrops fetalis in Folge intrauteriner B19V Infektion.
received 31.07.2014 accepted 14.10.2014 after revision Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1395538 Online-Publikation: 1.4.2015 Z Geburtsh Neonatol 2015; 219: 144–147 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0948-2393 Correspondence Dr. Silvia Welcker General Pediatrics and Neonatology UKGM Gießen Feulgenstraße12 35392 Gießen Germany [email protected]. uni-giessen.de
General Pediatrics and Neonatology, Gießen, UKGM Gießen, Germany Neonatolgy and Pediatric Intensive Care, University Medicine Greifswald, Greifswald, Germany
▼
Introduction
▼
Parvovirus B19 (B19V) infection is mainly asso ciated with rashes in school-aged children but also with fetal loss, acute arthritis, arthralgia and chronic anemia in immunodeficient patients. The incidence of seroconversion during pregnancy is estimated to be 1–1.5 %. In epidemic periods (every 3–6 years) the incidence increases up to 13 %. The course of infection during pregnancy can be total asymptomatic (30–50 %). Erythema infectiosum is seen in 30–40 % of cases. Peripheral polyarthropathy of the hands, wrists and knees may be the only manifestation. Vertical transmission occurs in 33–51 % of cases, even if the women may be asymptomatic. A fetal loss rate of 5–10 % is observed [1]. B19V is a potent inhibitor of hematopoiesis. Fetal complications are mainly due to the destruction of infected red blood cell precursors leading to severe fetal anemia. Several cellular receptors
▼
and co-receptors for parvovirus are also present in endothelial cells, placental tissue and fetal myocardium. Due to this, inflammation can lead to myocarditis and placentitis causing placental dysfunction [2]. Anemia (and in some cases myocarditis) may cause cardiac failure leading to hydropic or nonhydropic fetal death and stillbirth. The risk of dev eloping non-immune hydrops fetalis varies between 0–12.5 %. As a result of viral tropism for immature erythropoetic cells and the small fetal hematological reserve, the risk for fetal death and hydrops fetalis increases when the infection occurs prior to the 20th gestational week during the hepatic stage of hematopoiesis [2–4]. The fetal infection is unpredictable as demons trated by cases of twin pregnancies. There is no correlation between the presence of maternal symptoms and vertical transmission. Only abnormal ultrasound signs like nuchal translucency measurements and ductus venosus Dop-
Welcker S, Heckmann M. Non-Immune Hydrops fetalis due … Z Geburtsh Neonatol 2015; 219: 144–147
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
Schüsselwörter ▶ Hydrops fetalis ● ▶ Parvovirus B19 ● ▶ Frühgeborene ●
2
Case Report 145
Case Reports
▼
Case 1
The 31-year-old woman (gravida 2, para 0) remembered a common cold 6 weeks before ultrasound revealed a hydrops fetalis at 25 gestational weeks. B19V IgG, IgM and B19V PCR performed on mother’s serum proved positive. Cordocentesis with IUT and ascites puncture were performed at 24 + 6 weeks of gestation. After IUT of 50 mL blood, fetal hemoglobin level increased from 68 g/L to 120 g/L. Due to HELLP syndrome the infant was delivered by Cesarean section at 25 + 3 week [APGAR 3/6/8, arterial umbilical cord pH: 7.31, birth weight: 730 g (P25–50)]. After having received an emergency blood transfusion (13.7 mL/kg) in the delivery room, the initial hemoglobin was 135 g/L. Postnatal course was complicated by respiratory distress syndrome, PDA, persistent pulmonary hypertension with reduced left ventricular function treated with inhaled nitric oxide. In neonatal period no further transfusion due to the B19V infection was necessary. Postnatal cranial ultrasound revealed an intracranial hemorrhage (ICH) I ° but no periventricular leukomalacia (PVL). The neurology was unremarkable in the neonatal period. It suffered under septicemia and developed a retinopathy of prematurity (ROP) stage 3 and mild bronchopulmonary dysplasia (BPD). A failure to thrive was obvious during the course of treatment. At corrected age of 10 months the last cranial ultrasound showed no abnormality. At corrected age of 20 months a neurodevelopmental delay of 5 months and a mild CP was noticed. Cognitive function was assessed with the Kaufman Assessment Battery for Children (KABC) at the age of 4 years. His abilities were just within the normal range. His motor skills measured by Bayley
Scales of Infant Development were far below his developmental age. No further neuropediatric consultation took place. At the age of 9 years mild coordination and balance impairment was noticed. He attended third grade of school with special needs education due to a mild learning disability.
Case 2
A 33-year-old woman (gravida 3, para 2) was diagnosed with hydrops fetalis and ascites at 14th week of gestation. B19V serology performed on the mother’s serum proved positive. Due to pathological fetal cardiotocography the infant was delivered by Cesarean section at 26 + 3 week [APGAR 6/7/8; arterial umbilical cord pH: 7.1, birth weight: 870 g (P25–50)]. B19V DNA was isolated by PCR from umbilical cord blood and placenta. Anti-B19V IgG Western blot of the infant’s serum was positive too. The early perinatal period was complicated by severe recurrent anemia (initial hemoglobin: 43 g/L), so the child received 12 transfusions (10–13 mL/kg) in the first 2 months of life. He suffered from respiratory distress syndrome, PDA, persistent pulmonary hypertension treated with inhaled nitric oxide. Long term ventilation (67 days) and severe BPD followed. No ICH or PVL were noticed, neurology was normal. He developed ROP stage 1/2. A severe delay of early childhood development and severe failure to thrive were observed during the first years of life. At corrected age of 11 months the last cranial ultrasound showed no abnormality. He was able to talk first words and sit without help at the age of 2 years. At 3 years he could walk. At 6 years a severe learning disability and no age-appropriate motor skills were observed. Cognitive development was tested with KABC. His intellectual abilities were below or, respectively, far below average. At the age of 8 years he attended first grade with special needs education and school integration assistant. There was still an obvious impaired coordination and balance. KABC was performed again at 9 years. His cognitive development was far below average.
Discussion
▼
Data on long-term neurodevelopmental outcome after IUT for any indications are extremely limited. There are only a few studies on long-term neurodevelopmental outcome of survivors after hy▶ Table 1). drops fetalis caused by intrauterine B19V infection ( ● Miller et al. described normal neurodevelopmental outcome of 129 surviving infants at the age of 7–10 years. The outcome was measured by sending a questionnaire to the obstetricians or general practitioners. Only 3 of 129 examined survivors had deve loped fetal hydrops [10]. Dembinski et al. reported normal neurodevelopmental of 20 survivors of B19V induced fetal hydrops at the age of 13 months to 9 years of age. No independent effect on developmental quotient and intelligence quotient of minimum fetal hemoglobin or hematocrit, total number of IUT or gestational age at delivery was observed. This study was limited by a high lost-to-follow-up rate (35 %) [11]. 2 studies observed an increased abnormal neurodevelopmental outcome of survivors after B19V induced hydrops fetalis treated with IUT. De Jong et al. described a higher incidence of severe developmental delay and cerebral palsy of 28 patients at the age of 1.5–13 years compared with the Dutch normative population. Nagel et al. reported an increased incidence of severe neurodevelopmental prognosis in 12.5 % of 16 survivors after B19V
Welcker S, Heckmann M. Non-Immune Hydrops fetalis due … Z Geburtsh Neonatol 2015; 219: 144–147
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
pler velocimetry may predict fetal complications due to the presence of severe fetal anemia. Since there is no specific antiviral therapy or vaccine, only intrauterine red blood cell transfusion (IUT) can reduce the mortality rate. In most cases one transfusion is sufficient and the survival rate is up to 84 % [5]. Nevertheless, in contrast to other causes of fetal anemia and hydrops, cases of spontaneous reversal of hydrops fetalis have been observed due to the increase of fetal immune response [1]. In single cases maternal treatment with intravenous IgG was successful [6, 7]. A relation between fetal malformations after B19V infection has not been proven yet, although rare cases are described. Shortterm neurological complications including encephalopathy and severe central nervous system abnormalities like polymicrogyria and heterotopia have been reported too. A post-mortem examination of a fetus revealed multinucleated reactive microglia cells in the cerebral white matter and perivascular calcifications in the cerebral cortex, basal ganglia, thalamus and germinal layer. These findings suggest that immature fetal blood vessels permit infection of B19V causing perivascular inflammatory changes [2, 6, 8, 9]. Long-term developmental outcome after fetal B19V infection is therefore affected by fetal anemia and presumably direct infection of the CNS. However, the long-term consequences of surviving hydrops fetalis after B19V infection are not well known. Even less we know about those survivors being delivered preterm. There is only one single case report on long term outcome of an extremely preterm infant in more detail [7].
146 Case Report
Author
IUT
Gestional age (weeks)
Follow-up (years)
Neurodevelopmental outcome
Nagel (2007) [14]
1 1 1 1 3 11 9 15
0 1 0 1 2 11 9 15
32 34 28 + 3 > 37 ? > 37 25–36 > 37
2 1 0.6 4 7–10 1–9 1–9 0.5–8
de Jong (2012) [12]
1 28
1 28
32 32–41
1 1.5–13
Schoberer (2013) [7] Welcker (this study)
1 2
0 1
26 25 + 3 26 + 3
10 9
normal normal normal normal normal normal normal 5 (33 %) abnormal 10 (66 %) normal normal 3 (11 %) abnormal 25 (89 %) normal normal abnormal
Sheikh (1992) [16] Cameron (1997) [15] McNamara (1998) [17] Rodis (1998) [5] Miller (1998) [10] Dembinski (2002) [11]
Patient number
induced fetal hydrops treated with IUT. In one-third the neurodevelopmental status was abnormal at the age 0.5–8 years. Although the evidence is limited by small sample size and lack of structured long-term follow-up studies the risk of delayed neurodevelopment in long-term survivors after IUT for B19V infection appears to be increased. The underlying mechanism is still not fully understood. In comparison to long-term neurodevelopmental outcome of survivors requiring IUT for alloimmune anemia, the vast majority ( > 95 %) of the children have a normal neurodevelopmental outcome. However, in the LOTUS study the incidence of cerebral palsy and severe developmental delay in those children with fetal hydrops after red cell alloimmunization was slightly higher compared with the general population. This observation is in line with the reported rate after IUT for anemia caused by B19V infection. It leads to the conclusion that cerebral damage is induced by hypoxic-ischemic injury after severe fetal anemia and fetal hydrops. In contrast Nagel et al. and de Jong et al. found no relation between the minimum fetal hemoglobin, fetal acedemia and subsequent neurodevelopmental status, but this may result from the limited sample size. Like mentioned before some these authors also consider that the increased rate of neurodevelopmental delay could be related to cerebral injury induced by B19V itself [12–14]. Reports on infants that survived congenital B19V infection and were delivered preterm are very rare. Nagel et al. described a preterm of 32 weeks of gestation after B19V induced fetal hydrops treated with IUT that developed normally in the first year of life [14]. Cameron et al. reported on a survivor after B19V induced fetal hydrops treated with IUT that was delivered at 34 gestational weeks and also showed a normal development at the age of 2 years [15]. Sheikh et al. made 1 year of follow-up in a single survivor with spontaneously resolved hydrops delivered at 32 week of gestation. The infant developed normally too [16]. Only 3 studies mention extremely preterm infants. Dembinski et al. reported 9 preterms with a range between 25–36 weeks of gestation that survived B19V induced fetal hydrops treated with IUT. They showed no different development to term infants. However neurodevelopmental outcome of the extremely preterm infants was not discussed in more detail [11].
Schoberer et al. described a single case of a preterm at 26 completed weeks that survived hydrops fetalis caused by B19V without IUT. He showed a normal neurodevelopmental outcome with above-average school achievement at the age of 10 years [7]. McNamara et al. reported on a preterm at 28 + 3 gestational weeks that was delivered by an emergency Caesarean section due to gross fetal ascites, placental enlargement, and oligohydramnios. B19V DNA was subsequently detected in postnatal blood samples. It was only mentioned that the progress, reviewed at 5 and 8 corrected months of age, was remarkably good [17]. In our cases neurodevelopmental outcome of both extremely preterm infants was below average at the age of 9 years. They both suffered from hydrops fetalis. Preterm birth and a complicated postnatal course may have contributed to the outcome. In case 2 the child developed severe BPD with long-term ventilation. His developmental delay is more obvious. The slight difference in neurodevelopment may be also due to the fact that only in the first case IUT was performed, so the infant in case 2 suffered from severe anemia at birth. No follow-up cerebral imaging was made in both cases. It is not possible to distinguish between cerebral damage induced by prematurity or by B19V infection of the central nervous system.
Conclusion
▼
Neurodevelopmental outcome after congenital B19V infection especially for extremely preterm infants is not well known. The risk of neurodevelopment delay in long-term survivors appears to be increased. Prevention of fetal hydrops by timely detection and treatment may improve long-term outcome. To gain further insight in central nervous damage larger studies including longterm follow-up and cerebral imaging are needed.
References
1 Lamont RF, Sobel JD, Vaisbuch E et al. Parvovirus B19 infection in human pregnancy. BJOG 2011; 118: 175–186 2 Mylonas I, Gutsche S, Anton G et al. Parvovirus B19 infection during pregnancy. Z Geburtshilfe Neonatol 2007; 211: 60–68 3 Enders M, Weidner A, Zoellner I et al. Fetal morbidity and mortality after acute human parvovirus B19 infection in pregnancy: prospective evaluation of 1018 cases. Prenat Diagn 2004; 24: 513–518 4 Puccetti C, Contoli M, Bonvicini F et al. Parvovirus B19 in pregnancy: possible consequences of vertical transmission. Prenat Diagn 2012; 32: 897–902
Welcker S, Heckmann M. Non-Immune Hydrops fetalis due … Z Geburtsh Neonatol 2015; 219: 144–147
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Table 1 Neurodevelopmental outcome after non-immune hydrops fetalis due to congenital B19V Infection.
Case Report 147 12 De Jong EP, Lindenburg IT, van Klink JM et al. Intrauterine transfusion for parvovirus B19 infection: long-term neurodevelopmental outcome. Am J Obstet Gynecol 2012; 206: 204.e201–204.e205 13 Lindenburg IT, Smits-Wintjens VE, van Klink JM et al. Long-term neurodevelopmental outcome after intrauterine transfusion for hemoly tic disease of the fetus/newborn: the LOTUS study. Am J Obstet Gyneco 2012; 206: 141.e141–141.e148 14 Nagel HT, de Haan TR, Vandenbussche FP et al. Long-term outcome after fetal transfusion for hydrops associated with parvovirus B19 infection. Obstet Gynecol 2007; 109: 42–47 15 Cameron AD, Swain S, Patrick WJ. Human parvovirus B19 infection associated with hydrops fetalis. Aust N Z J Obstet Gynaecol 1997; 37: 316–319 16 Sheikh AU, Ernest JM, O’Shea M. Long-term outcome in fetal hydrops from parvovirus B19 infection. Am J Obstet Gynecol 1992; 167: 337–341 17 McNamara PJ, Ramanan R. Survival of a preterm neonate with late onset hydrops fetalis due to parvovirus B19 infection. Acta Paediatr 1998; 87: 1088–1089
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
5 Rodis JF, Borgida AF, Wilson M et al. Management of parvovirus infection in pregnancy and outcomes of hydrops: a survey of members of the Society of Perinatal Obstetricians. Am J Obstet Gynecol 1998; 179: 985–988 6 de Jong EP, Walther FJ, Kroes AC et al. Parvovirus B19 infection in pregnancy: new insights and management. Prenat Diagn 2011; 31: 419–425 7 Schoberer M, Rink A, Rath W et al. Ballantyne syndrome and congenital anaemia associated with Parvovirus B19 infection: case report and review. Z Geburtshilfe Neonatol 2013; 217: 183–188 8 Isumi H, Nunoue T, Nishida A et al. Fetal brain infection with human parvovirus B19. Pediatr Neurol 1999; 21: 661–663 9 Pistorius LR, Smal J, de Haan TR et al. Disturbance of cerebral neuronal migration following congenital parvovirus B19 infection. Fetal Diagn Ther 2008; 24: 491–494 10 Miller E, Fairley CK, Cohen BJ et al. Immediate and long term outcome of human parvovirus B19 infection in pregnancy. Br J Obstet Gynaecol 1998; 105: 174–178 11 Dembinski J, Haverkamp F, Maara H et al. Neurodevelopmental outcome after intrauterine red cell transfusion for parvovirus B19-induced fetal hydrops. BJOG 2002; 109: 1232–1234
Welcker S, Heckmann M. Non-Immune Hydrops fetalis due … Z Geburtsh Neonatol 2015; 219: 144–147
Non-immune Hydrops fetalis due to Parvovirus B19 Infection in 2 Extremely Preterm Infants: Perinatal Management and Long-term Neurodevelopmental Outcome Nicht-immuner Hydrops fetalis in Folge Parvovirus B19 Infektion bei 2 extrem frühgeborenen Kindern: Perinatales Management und Langzeit-Outcome Authors
S. Welcker1, M. Heckmann2
Affiliations
1
Key words ▶ Hydrops fetalis ● ▶ parvovirus B19 ● ▶ preterm infants ●
Abstract
Zusammenfassung
Parvovirus B19 (B19V) infection during pregnancy can lead to fetal damage and even fetal loss. In some cases a severe fetal anemia with hydrops fetalis occurs. An intrauterine red blood cell transfusion can reduce the mortality rate. Neuro developmental outcome after fetal B19V infection is affected by fetal anemia and presumably direct infection of the CNS. There are only a few studies on long-term neurodevelopmental outcome after B19V infection induced hydrops fetalis. There are hardly any long-term data especially in preterm infants. We report on the long-term outcomes of 2 extremely preterm children after non-immune hydrops fetalis due to intrauterine B19V Infection.
Eine Parvovirus B19 (B19V) Infektion in der Schwangerschaft kann eine Schädigung des Feten und sogar eine Fehlgeburt zur Folge haben. In einigen Fällen tritt eine schwere fetale Anämie mit Hydrops fetalis auf, dessen Mortalität durch eine intrauterine Bluttransfusion gesenkt werden kann. Das neurologische Outcome wird nicht nur durch das Auftreten eines Hydrops fetalis beeinflusst sondern vermutlich auch durch direkte Infektion des ZNS. Über das Langzeit-Outcome nach B19V-Infektion induzierten Hydrops fetalis gibt es nur wenige Studien. Besonders bei Frühgeborenen liegen kaum Langzeitdaten vor. Wir berichten nun über das Langzeit-Outcome zweierextrem frühgeborener Kinder nach nichtimmunem Hydrops fetalis in Folge intrauteriner B19V Infektion.
received 31.07.2014 accepted 14.10.2014 after revision Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1395538 Online-Publikation: 1.4.2015 Z Geburtsh Neonatol 2015; 219: 144–147 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0948-2393 Correspondence Dr. Silvia Welcker General Pediatrics and Neonatology UKGM Gießen Feulgenstraße12 35392 Gießen Germany [email protected]. uni-giessen.de
General Pediatrics and Neonatology, Gießen, UKGM Gießen, Germany Neonatolgy and Pediatric Intensive Care, University Medicine Greifswald, Greifswald, Germany
▼
Introduction
▼
Parvovirus B19 (B19V) infection is mainly asso ciated with rashes in school-aged children but also with fetal loss, acute arthritis, arthralgia and chronic anemia in immunodeficient patients. The incidence of seroconversion during pregnancy is estimated to be 1–1.5 %. In epidemic periods (every 3–6 years) the incidence increases up to 13 %. The course of infection during pregnancy can be total asymptomatic (30–50 %). Erythema infectiosum is seen in 30–40 % of cases. Peripheral polyarthropathy of the hands, wrists and knees may be the only manifestation. Vertical transmission occurs in 33–51 % of cases, even if the women may be asymptomatic. A fetal loss rate of 5–10 % is observed [1]. B19V is a potent inhibitor of hematopoiesis. Fetal complications are mainly due to the destruction of infected red blood cell precursors leading to severe fetal anemia. Several cellular receptors
▼
and co-receptors for parvovirus are also present in endothelial cells, placental tissue and fetal myocardium. Due to this, inflammation can lead to myocarditis and placentitis causing placental dysfunction [2]. Anemia (and in some cases myocarditis) may cause cardiac failure leading to hydropic or nonhydropic fetal death and stillbirth. The risk of dev eloping non-immune hydrops fetalis varies between 0–12.5 %. As a result of viral tropism for immature erythropoetic cells and the small fetal hematological reserve, the risk for fetal death and hydrops fetalis increases when the infection occurs prior to the 20th gestational week during the hepatic stage of hematopoiesis [2–4]. The fetal infection is unpredictable as demons trated by cases of twin pregnancies. There is no correlation between the presence of maternal symptoms and vertical transmission. Only abnormal ultrasound signs like nuchal translucency measurements and ductus venosus Dop-
Welcker S, Heckmann M. Non-Immune Hydrops fetalis due … Z Geburtsh Neonatol 2015; 219: 144–147
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
Schüsselwörter ▶ Hydrops fetalis ● ▶ Parvovirus B19 ● ▶ Frühgeborene ●
2
Case Report 145
Case Reports
▼
Case 1
The 31-year-old woman (gravida 2, para 0) remembered a common cold 6 weeks before ultrasound revealed a hydrops fetalis at 25 gestational weeks. B19V IgG, IgM and B19V PCR performed on mother’s serum proved positive. Cordocentesis with IUT and ascites puncture were performed at 24 + 6 weeks of gestation. After IUT of 50 mL blood, fetal hemoglobin level increased from 68 g/L to 120 g/L. Due to HELLP syndrome the infant was delivered by Cesarean section at 25 + 3 week [APGAR 3/6/8, arterial umbilical cord pH: 7.31, birth weight: 730 g (P25–50)]. After having received an emergency blood transfusion (13.7 mL/kg) in the delivery room, the initial hemoglobin was 135 g/L. Postnatal course was complicated by respiratory distress syndrome, PDA, persistent pulmonary hypertension with reduced left ventricular function treated with inhaled nitric oxide. In neonatal period no further transfusion due to the B19V infection was necessary. Postnatal cranial ultrasound revealed an intracranial hemorrhage (ICH) I ° but no periventricular leukomalacia (PVL). The neurology was unremarkable in the neonatal period. It suffered under septicemia and developed a retinopathy of prematurity (ROP) stage 3 and mild bronchopulmonary dysplasia (BPD). A failure to thrive was obvious during the course of treatment. At corrected age of 10 months the last cranial ultrasound showed no abnormality. At corrected age of 20 months a neurodevelopmental delay of 5 months and a mild CP was noticed. Cognitive function was assessed with the Kaufman Assessment Battery for Children (KABC) at the age of 4 years. His abilities were just within the normal range. His motor skills measured by Bayley
Scales of Infant Development were far below his developmental age. No further neuropediatric consultation took place. At the age of 9 years mild coordination and balance impairment was noticed. He attended third grade of school with special needs education due to a mild learning disability.
Case 2
A 33-year-old woman (gravida 3, para 2) was diagnosed with hydrops fetalis and ascites at 14th week of gestation. B19V serology performed on the mother’s serum proved positive. Due to pathological fetal cardiotocography the infant was delivered by Cesarean section at 26 + 3 week [APGAR 6/7/8; arterial umbilical cord pH: 7.1, birth weight: 870 g (P25–50)]. B19V DNA was isolated by PCR from umbilical cord blood and placenta. Anti-B19V IgG Western blot of the infant’s serum was positive too. The early perinatal period was complicated by severe recurrent anemia (initial hemoglobin: 43 g/L), so the child received 12 transfusions (10–13 mL/kg) in the first 2 months of life. He suffered from respiratory distress syndrome, PDA, persistent pulmonary hypertension treated with inhaled nitric oxide. Long term ventilation (67 days) and severe BPD followed. No ICH or PVL were noticed, neurology was normal. He developed ROP stage 1/2. A severe delay of early childhood development and severe failure to thrive were observed during the first years of life. At corrected age of 11 months the last cranial ultrasound showed no abnormality. He was able to talk first words and sit without help at the age of 2 years. At 3 years he could walk. At 6 years a severe learning disability and no age-appropriate motor skills were observed. Cognitive development was tested with KABC. His intellectual abilities were below or, respectively, far below average. At the age of 8 years he attended first grade with special needs education and school integration assistant. There was still an obvious impaired coordination and balance. KABC was performed again at 9 years. His cognitive development was far below average.
Discussion
▼
Data on long-term neurodevelopmental outcome after IUT for any indications are extremely limited. There are only a few studies on long-term neurodevelopmental outcome of survivors after hy▶ Table 1). drops fetalis caused by intrauterine B19V infection ( ● Miller et al. described normal neurodevelopmental outcome of 129 surviving infants at the age of 7–10 years. The outcome was measured by sending a questionnaire to the obstetricians or general practitioners. Only 3 of 129 examined survivors had deve loped fetal hydrops [10]. Dembinski et al. reported normal neurodevelopmental of 20 survivors of B19V induced fetal hydrops at the age of 13 months to 9 years of age. No independent effect on developmental quotient and intelligence quotient of minimum fetal hemoglobin or hematocrit, total number of IUT or gestational age at delivery was observed. This study was limited by a high lost-to-follow-up rate (35 %) [11]. 2 studies observed an increased abnormal neurodevelopmental outcome of survivors after B19V induced hydrops fetalis treated with IUT. De Jong et al. described a higher incidence of severe developmental delay and cerebral palsy of 28 patients at the age of 1.5–13 years compared with the Dutch normative population. Nagel et al. reported an increased incidence of severe neurodevelopmental prognosis in 12.5 % of 16 survivors after B19V
Welcker S, Heckmann M. Non-Immune Hydrops fetalis due … Z Geburtsh Neonatol 2015; 219: 144–147
Downloaded by: University of Pennsylvania Libraries. Copyrighted material.
pler velocimetry may predict fetal complications due to the presence of severe fetal anemia. Since there is no specific antiviral therapy or vaccine, only intrauterine red blood cell transfusion (IUT) can reduce the mortality rate. In most cases one transfusion is sufficient and the survival rate is up to 84 % [5]. Nevertheless, in contrast to other causes of fetal anemia and hydrops, cases of spontaneous reversal of hydrops fetalis have been observed due to the increase of fetal immune response [1]. In single cases maternal treatment with intravenous IgG was successful [6, 7]. A relation between fetal malformations after B19V infection has not been proven yet, although rare cases are described. Shortterm neurological complications including encephalopathy and severe central nervous system abnormalities like polymicrogyria and heterotopia have been reported too. A post-mortem examination of a fetus revealed multinucleated reactive microglia cells in the cerebral white matter and perivascular calcifications in the cerebral cortex, basal ganglia, thalamus and germinal layer. These findings suggest that immature fetal blood vessels permit infection of B19V causing perivascular inflammatory changes [2, 6, 8, 9]. Long-term developmental outcome after fetal B19V infection is therefore affected by fetal anemia and presumably direct infection of the CNS. However, the long-term consequences of surviving hydrops fetalis after B19V infection are not well known. Even less we know about those survivors being delivered preterm. There is only one single case report on long term outcome of an extremely preterm infant in more detail [7].
146 Case Report
Author
IUT
Gestional age (weeks)
Follow-up (years)
Neurodevelopmental outcome
Nagel (2007) [14]
1 1 1 1 3 11 9 15
0 1 0 1 2 11 9 15
32 34 28 + 3 > 37 ? > 37 25–36 > 37
2 1 0.6 4 7–10 1–9 1–9 0.5–8
de Jong (2012) [12]
1 28
1 28
32 32–41
1 1.5–13
Schoberer (2013) [7] Welcker (this study)
1 2
0 1
26 25 + 3 26 + 3
10 9
normal normal normal normal normal normal normal 5 (33 %) abnormal 10 (66 %) normal normal 3 (11 %) abnormal 25 (89 %) normal normal abnormal
Sheikh (1992) [16] Cameron (1997) [15] McNamara (1998) [17] Rodis (1998) [5] Miller (1998) [10] Dembinski (2002) [11]
Patient number
induced fetal hydrops treated with IUT. In one-third the neurodevelopmental status was abnormal at the age 0.5–8 years. Although the evidence is limited by small sample size and lack of structured long-term follow-up studies the risk of delayed neurodevelopment in long-term survivors after IUT for B19V infection appears to be increased. The underlying mechanism is still not fully understood. In comparison to long-term neurodevelopmental outcome of survivors requiring IUT for alloimmune anemia, the vast majority ( > 95 %) of the children have a normal neurodevelopmental outcome. However, in the LOTUS study the incidence of cerebral palsy and severe developmental delay in those children with fetal hydrops after red cell alloimmunization was slightly higher compared with the general population. This observation is in line with the reported rate after IUT for anemia caused by B19V infection. It leads to the conclusion that cerebral damage is induced by hypoxic-ischemic injury after severe fetal anemia and fetal hydrops. In contrast Nagel et al. and de Jong et al. found no relation between the minimum fetal hemoglobin, fetal acedemia and subsequent neurodevelopmental status, but this may result from the limited sample size. Like mentioned before some these authors also consider that the increased rate of neurodevelopmental delay could be related to cerebral injury induced by B19V itself [12–14]. Reports on infants that survived congenital B19V infection and were delivered preterm are very rare. Nagel et al. described a preterm of 32 weeks of gestation after B19V induced fetal hydrops treated with IUT that developed normally in the first year of life [14]. Cameron et al. reported on a survivor after B19V induced fetal hydrops treated with IUT that was delivered at 34 gestational weeks and also showed a normal development at the age of 2 years [15]. Sheikh et al. made 1 year of follow-up in a single survivor with spontaneously resolved hydrops delivered at 32 week of gestation. The infant developed normally too [16]. Only 3 studies mention extremely preterm infants. Dembinski et al. reported 9 preterms with a range between 25–36 weeks of gestation that survived B19V induced fetal hydrops treated with IUT. They showed no different development to term infants. However neurodevelopmental outcome of the extremely preterm infants was not discussed in more detail [11].
Schoberer et al. described a single case of a preterm at 26 completed weeks that survived hydrops fetalis caused by B19V without IUT. He showed a normal neurodevelopmental outcome with above-average school achievement at the age of 10 years [7]. McNamara et al. reported on a preterm at 28 + 3 gestational weeks that was delivered by an emergency Caesarean section due to gross fetal ascites, placental enlargement, and oligohydramnios. B19V DNA was subsequently detected in postnatal blood samples. It was only mentioned that the progress, reviewed at 5 and 8 corrected months of age, was remarkably good [17]. In our cases neurodevelopmental outcome of both extremely preterm infants was below average at the age of 9 years. They both suffered from hydrops fetalis. Preterm birth and a complicated postnatal course may have contributed to the outcome. In case 2 the child developed severe BPD with long-term ventilation. His developmental delay is more obvious. The slight difference in neurodevelopment may be also due to the fact that only in the first case IUT was performed, so the infant in case 2 suffered from severe anemia at birth. No follow-up cerebral imaging was made in both cases. It is not possible to distinguish between cerebral damage induced by prematurity or by B19V infection of the central nervous system.
Conclusion
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Neurodevelopmental outcome after congenital B19V infection especially for extremely preterm infants is not well known. The risk of neurodevelopment delay in long-term survivors appears to be increased. Prevention of fetal hydrops by timely detection and treatment may improve long-term outcome. To gain further insight in central nervous damage larger studies including longterm follow-up and cerebral imaging are needed.
References
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Table 1 Neurodevelopmental outcome after non-immune hydrops fetalis due to congenital B19V Infection.
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