Case Report 183
Ballantyne Syndrome and Congenital Anaemia Associated with Parvovirus B19 Infection: Case Report and Review Ballantyne Syndrom und konnatale Anämie durch Parvovirus B19: Kasuistik und Literaturübersicht M. Schoberer1, A. Rink2, W. Rath2, T. Orlikowsky1 1
Affiliations
2
Key words ▶ Ballantyne syndrome ● ▶ triple edema ● ▶ mirror syndrome ● ▶ preeclampsia ● ▶ fetal hydrops ● ▶ Parvovirus ● ▶ congenital anaemia ● Schlüsselwörter ▶ Ballantyne Syndrom ● ▶ Triple-Ödem ● ▶ Mirror-Syndrom ● ▶ Präeklampsie ● ▶ Hydrops fetalis ● ▶ Parvovirus ● ▶ kongenitale Anämie ●
received accepted after revision
17.04.2012 04.10.2012
Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1355349 Z Geburtsh Neonatol 2013; 217: 183–188 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0948-2393 Correspondence Dr. med. Mark Schoberer Klinik für Kinder- und Jugendmedizin Sektion Neonatologie Pauwelsstrasse 30 52074 Aachen Germany Tel.: + 49/241/803 6117 Fax: + 49/241/808 2436 [email protected]
Klinik für Kinder- und Jugendmedizin, Sektion Neonatologie, Universitätsklinikum Aachen, Aachen, Germany Frauenklinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Aachen, Aachen, Germany
Abstract
Zusammenfassung
Acute maternal Parvovirus B19 infection affects about 1 % of all pregnancies worldwide. Diaplacental transmission of Parvovirus B19 during the second trimester can cause complications like foetal hydrops, premature delivery or foetal loss in about 20–30 % of these pregnancies, whereas the majority of maternal infections remain clinically silent. In individual cases, foetoplacental hydrops (of various origins) can trigger a rare form of Preeclampsia in the pregnant woman. The developing maternal oedema in this situation apparently “mirrors” the hydropic state of the foetus. The symptom triad of foetal hydrops, foetoplacental oedema and maternal anasarca defines Ballantyne syndrome. We report a case of Parvovirus-induced Ballantyne syndrome including a 10-year follow-up of mother and child. While the mother recovered rapidly after (preterm) delivery, the infection complicated the first months of life of the neonate. Congenital transfusion-dependent red cell aplasia and cholestatic hepathopathy took a chronic course but resolved under IVIG treatment. Followup now finds both the former neonate and the mother entirely recovered. Current knowledge on Ballantyne syndrome as well as perigestational Parvovirus infections including congenital anaemia is briefly reported and pathophysiological hypotheses are discussed.
Akute Infektionen mit Parvovirus B19 betreffen weltweit etwa 1 % der Schwangerschaften. Eine diaplazentare Übertragung des Erregers im zweiten Trimenon führt in rund 20–30 % der Fälle zu Komplikationen wie Hydrops Fetalis, Frühgeburtlichkeit oder Spätabort, wohingegen die Mehrzahl der maternalen Infektionen klinisch stumm verläuft. In Einzelfällen kann ein fetoplazentarer Hydrops (egal welchen Ursprungs) bei der Schwangeren eine seltene Form der Präeklampsie auslösen. Maternale Anasarka „spiegeln“ in dieser Situation den Hydrops des Feten. Diese Symptomentrias fetaler Hydrops, Plazentaödem und maternale Anasarka definiert das Ballantyne Syndrom. Wir berichten die Kasuistik eines durch Parvovirus induzierten Ballantyne Syndroms einschließlich einer 10-jährigen Nachbeobachtung von Mutter und Kind. Während sich die Mutter nach der (vorzeitigen) Entbindung rasch erholte, verlief die Infektion bei dem Frühgeborenen langwierig und kompliziert: Sowohl eine kongenitale, transfusionspflichtige aplastische Anämie als auch eine cholestatische Hepatopathie nahmen einen chronischen Verlauf und bildeten sich erst nach rund einem Jahr unter intravenöser Immunglobulintherapie zurück. In der Nachbeobachtung ist die Erkrankung bei Mutter und Kind folgenlos ausgeheilt. Der Artikel gibt eine Übersicht über den aktuellen Stand des Wissens bezüglich des Ballantyne Syndroms und gestationsassoziierter Parvovirus Infektionen. Pathophysiologische Zusammenhänge und Hypothesen werden diskutiert.
Case Report Ballantyne syndrome in a 36-year-old woman
temporal headache, marked oedema, weight gain, proteinuria and arterial hypertension. Blood type (A Rh. pos.) was not indicative for immunological incompatibility.
The 36-year-old gravida 2, para 1 was admitted to our hospital at 26 + 0 weeks of gestation because of suspected preeclampsia with mild
Ballantyne Criteria: The patient had experienced a 17-kg weight gain during pregnancy.
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Schoberer M et al. Ballantyne Syndrome and Congenital … Z Geburtsh Neonatol 2013; 217: 183–188
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Authors
184 Case Report
(230 μmol/L) at the age of 6 months. Hypoproteinaemia and disturbed coagulation tests required ongoing substitution of albumin, fresh frozen plasma and antithrombin. Extrahepatic cholestasis was excluded by hepatobiliary scintigraphy. Erythropoietin was routinely administered as prophylaxis against anaemia of prematurity until the postmenstrual age (PMA) of 36 weeks. A marked aggravation of cholestasis developed after erythropoietin therapy was reinstituted at the age of 4 months in order to reduce transfusion dependency.
IVIG treatment: A first therapeutic trial with intravenously administered immunoglobulins (IVIG) at a dose of 400 mg/kg/d on 5 consecutive days during the third week of life remained ineffective. However, repeated immunoglobulin pulses of 400 mg/kg given monthly from the sixth to tenth month of life proved to be beneficial. Anaemia and cholestasis resolved. Because anaemia recurred after a 3-month trial discontinuation of therapy, immunoglobulin treatment was reinstituted and continued up to the age of 18 months. The patient remains free of symptoms since, although Parvovirus DNA was still detectable at the age of 22 months. 4 months later the Parvovirus PCR examination was negative for the first time and has remained so since.
Hydrops and congenital anaemia followed by cholestatic hepatopathy in the preterm infant The early perinatal period in the newborn was complicated by prematurity (gestational age was 26 completed weeks), hydrops and anaemia. Initial haemoglobin was 46 g/L, haematocrit was 0.13. An immediate red cell transfusion was performed. Parvovirus B19-DNA was isolated by polymerase chain reaction (PCR) from ascites, serum and bone marrow and thus clearly identified as a non-immunological origin of hydrops and anaemia. Echocardiographic examination showed myocardial dilation with preserved contractility.
Fig. 1 Hydropic placenta (diameter 76 mm).
Myelosuppression and congenital anaemia: The patient remained transfusion-dependent for 1 year and received a total of 19 erythrocyte concentrates. A bone-marrow aspirate performed at the age of 3 months displayed the pathognomonic pattern of giant pronormoblasts and the absence of maturing ▶ Fig. 2). Thrombocytopenia was treated erythroid precursors (● by substitution of 9 thrombocyte concentrates in the first 4 weeks of live but thrombopoesis recovered spontaneously thereafter. Hepatopathy: The clinical course became increasingly complicated by the development of a cholestatic hepatopathy. Clinical features were hepatomegaly, ascites and marked jaundice with an elevation of conjugated bilirubin (BC) up to 13.4 mg/dL
Fig. 2 Bone-marrow smear obtained at the age of 3 months: vacuolated giant pronormoblast.
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Daily urine output was diminished to 600 mL, blood pressure rose to 145/90 mmHg. Ultrasound examination revealed placen▶ Fig. 1) and foetal tal hydrops (max. placental diameter: 8 cm, ● ascites as well as pericardial effusions. Proteinuria was 3 g/day, creatinine clearance was reduced to 59 mL/min. Plasma proteins constantly dropped from 52 g/L on admission to 38 g/L in part due to renal wasting but also due to haemodilution. Haemoglobin decreased from 104 g/L on admission to 86 g/L 2 days later, platelet count fell from 109 G/L to 82 G/L in the same period. Serum-hCG exceeded the normal range for the late 2nd term by a 9-fold increase to 904 215 U/L. Maternal blood type (A Rh. pos.) was not indicative for immunological incompatibility. Foetal congestive heart failure and anatomic abnormalities were precluded by foetal ultrasound. Doppler velocimetry demonstrated a flow acceleration in foetal aorta and pulmonary arteries. TORCH screening gave no evidence of an acute infection. Maternal serum was found to be positive for Parvovirus-specific IgG, but negative for IgM, a pattern which was initially interpreted as serostatus after subsided infection. Parvovirus infection was finally proven by polymerase chain reaction (PCR) amplified detection of Parvovirus DNA in maternal serum. The examination had been performed after the virus-genome was isolated from foetal blood and ascites while serial parvovirus IgM examinations in maternal serum had remained negative. 2 days after admission, the progressive preeclampsia and foetal distress with a 5 BPM variability prompted a Caesarean section. Antenatal steroid treatment had been performed with intramuscular betamethasone injections. Renal function in the mother recovered gradually. Oliguria turned into polyuria 3 days after delivery (urine output > 3 L/d). All laboratory test abnormalities fully resolved over the next 2 weeks. Arterial blood pressure normalized under metoprolol treatment. The patient fully recovered from preeclampsia soon after discharge and remains free of symptoms since then.
Case Report 185 Table 1 Overview of published cases of Ballantyne syndrome.
Paternoster et al. Lobato et al. Heyborne et al. Gherman et al. Carbillon et al. Dorman et al. van Selm et al.
Maternal age
Previous
No. of
Reason for
GA at onset of
(years)
pregnancies
foetuses
hydrops
Hydrops (weeks)
37 24 45 28 38
2
singleton singleton twins singleton singleton singleton 3 cases of singletons
idiopathic Rh alloimunisation idiopathic chorioangioma Ebstein anomaly chorioangioma immunological in all cases
28 28 16 25 30
stillbirth
Pt 1: 22 Pt 2: 25 Pt 3: 28
Pt 1: foetal death Pt 2: foetal death Pt 3: foetal death
singleton triplets, one acardius
aneurysm of Galens vein acardius
23
singleton 2 cases of singletons
CMV infection PB 19 infection
29
acardius died under birth. one child survived 13 days, one child discharged healthy death after resuscitation
1 1 4
Pt 1: 39 Pt 2: 24 Pt 3: 29
Pt 1: 4 Pt 2: nn Pt 3: 1
26
none
Rana et al. Proust et al.
29
1
Brochot et al. Hayashi et al.
32 33
none 1
twins
PB 19 infection TTTS
22 25
Vidaeff et al. Midgley et al. Duthie et al.
26 25 34
2 none 1
singleton singleton singleton
idiopathic fetal tachycardia PB 19 infection
31 27
Ordorica et al. Matsubara et al.
Survival 20 days discharged healthy 1 foetocide 16th wk, 1 survivor
foetocide in 36th week* foetal death of donor at 25 2/7, 10 d survival of acceptor discharged healthy discharged healthy discharged healthy
*Due to path. MRI scan after complete reversal of Ballantyne syndrome GA = gestational age; TTTS = twin to twin transfusion syndrome
Long-term-outcome: The patient, now aged 10 years has persistently recovered from the congenital infection: He is free of any residuals and shows excellent performance in psychomotor and somatic development tests as well as above-average school achievement.
Discussion
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Ballantyne syndrome John William Ballantyne first summarized the clinical properties of the syndrome in 1892 [1]. Mandatory features are foetal and placental hydrops in combination with maternal anasarca. “Maternal hydrops syndrome” [2], “pseudotoxemia” [3] and “triple oedema syndrome” [4] are synonymously used terms. The notation “mirror syndrome” [5] indicates that the mother virtually “mirrors” foetal symptoms of severe hydrops. The diagnosis was originally restricted to cases associated with rhesus isoimmunization [6] but has been extended to non-immunological causes since it has become clear that these can likewise induce the triad. Published to date are Ebstein’s anomaly [7], foetal arrhythmias [6], placental chorioangioma [8, 9], aneurysm of Galen’s vein [10], intrauterine infections, e. g., syphilis, cytomegalovirus or human Parvovirus infection [11, 12]. The clinical triad of peripheral oedema, arterial hypertension and proteinuria makes Ballantyne syndrome a variant of preeclampsia. A distinct feature of this variant is a close pathogenetic link to placental hydrops. The large spectrum of possible triggers for foetoplacental hydrops including placental chorioangi▶ Table 1) implies that placental swelling itself rather than oma (● the underlying condition is the original trigger of maternal preeclampsia. Resolution of the foetoplacental oedema whether it occurs spontaneously [13], by intrauterine transfusion [11], elimination of foetal arrhythmias [6] or foetal death of affected multiples [14, 15] results in full restitution of maternal syptoms.
The causative role of hyperplacentation in the genesis of this specific form of preeclampsia however is not fully understood. Glomerular edotheliosis is the pathognomonic renal bioptic finding in preeclampsia, making it the most common glomerular disease in the world [16]. It is characterized by a loss of endothelial fenestrae and by glomerular endothelial swelling with occlusion of the capillary lumen. The absence of endotheliosis in the renal biopsy of one Ballantyne-patient reported by Quagliarello et al. [12] has been interpreted as an indicator to a distinctive pathophysiology of proteinuric hypertension in this group of patients. This view is challenged by the finding, that soluble fmslike tyrosin-kinase (sFlt1) an incomplete circulating VEGF receptor is likewise elevated in Ballyntyne syndrome as in “classical” cases of preeclampsia without hyperplacentation. VEGF deprivation of glomerular endothelial cells caused by the circulating receptor leads to cellular injury and disruption of the filtration apparatus with subsequent proteinuria [16]. The non-haemolytic dilutional anaemia that we observed in our patient is a distinctive feature of Ballantyne syndrome compared to “classical” preeclampsia. The expansion of blood volume results from high maternal serum levels of vasopressin and atrial natriuretic factor [7]. An excess of human chorionic gonadotropin (HCG) appears to be another specific feature of Ballantyne syndrome. The level in our patient exceeded 9 times the anticipated normal value [17]. Colwill et al. reported elevated serum HCG levels in 3 cases of Ballantyne syndrome [18]. In vitro experimentation has identified 3 factors that can influence trophoblastic HCG production: an increased amount of syncytiotrophoblastic cells [19], prolonged states of trophoblastic hypoxaemia [20] and inflammatory cytokines stimulating HCG synthesis [21]. During early pregnancy deficient placental angiogenesis and neovascularization can induce placental ischaemia by an inadequate conversion of the spiral arteries [22]. The syncytiotrophoblast responds to impaired perfusion by increasing the proliferation rate and the amount of secreted HCG [23].
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Autor
186 Case Report
Perigestational Parvovirus B19 infections affect 1 % of pregnancies worldwide [24]. The rate may rise up to 13 % during epidemics, which occur every 4–5 years. Most of the infections follow exposure from the pregnant womens’ own children [25, 26]. Immunoglobulin G seroconversion before conception grants immunity against the infection. It is found in 50–70 % of adult women [24, 25, 27, 28], leaving one third to half of pregnant women susceptible for the infection. If acute Parvovirus infection complicates pregnancy, vertical transmission rates are estimated to be 30–50 % [26, 28, 29] or may be even higher [30]. Intrauterine Parvovirus B19 infection can cause spontaneous abortion [24], especially during the first trimester [29, 31]. Stillbirth without hydrops occurs mainly from the late second trimester to term and may account for up to 15 % of all cases of foetal deaths [27]. Parvovirus is known to cause non-immunological foetal hydrops since 1984 [32] and has been observed in 18 % of such cases [33]. Hydrops is a typical complication of vertical transmission during the second trimester [28, 29, 34]. While affected individuals may experience severe complications, the overall risk of a clinically overt disease appears to be rare, even after vertical transmission. Miller et al. report a 9 % risk of foetal loss in a prospective cohort study of 427 pregnant women with confirmed B19 infection [34]. The spontaneous resolution of hydrops and the following delivery of symptomfree newborns at term have been repeatedly reported, especially after intrauterine red cell transfusion [35, 36]. Long-term sequelae in surviving children have been rarely observed in large follow-up studies [29, 34, 37]. Therefore termination of affected pregnancies cannot be routinely advocated. Management plans for pregnant women after Parvovirus exposition or serologically proven infection draw on identification of the source of exposure, maternal serological testing and targeted foetal ultrasound examinations for 6–14 weeks after exposure [35, 38, 39]. Inrauterine blood transfusions play the essential role in the management of (anaemia related) foetal hydrops and have been proven to improve survival [6, 40–42] Little information exists regarding the benefits of maternal IVIG treatment if acute Parvovirus infection occurs during pregnancy. Nevertheless such an approach has been advocated [43]. Matsuda et al. reported the successful treatment of foetal hydrops by injection of a B19-IgGrich immunoglobulin into the foetal peritoneal cavity [44]. Immunologically mediated foetal haemolysis usually causes hydrops only when haematocrit values fall short of 0.15 L/L. Foetal Parvovirus infection in contrast can trigger hydrops even in the presence of only mild anaemia, especially if myocardial affection triggers congestive heart failure. Only few data have been published regarding the long-term outcome of children affected by parvovirus-induced foetal hydrops. Nagel et al. report a 6-months to 8-years follow-up of 16 survivors. They report a delay of psychomotor development in 5 of these children, 3 of them with mild and 2 with severe degrees [45]. It is most likely that such mental impairment is not attributable to the foetal infection itself but its secondary complications hydrops, anaemia and prematuritiy. Rodis et al. found no differences in psychomotor development between 108 survivors of pregnancies complicated by serologically proven new-onset Parvovirus infection as compared to 93 controls in whom maternal serostatus confirmed past infection [46].
Congenital anaemia induced by intrauterine Parvovirus B19 infection Globoside, a neutral glycoprotein, acts as cellular receptor in Parvovirus infections. It is mainly expressed on erythroid precursor cells but is also found on thrombopoetic and myeloic precursors, as well as placental cells and foetal myocardial cells. Clinical and histopathological findings confirm the strong tropism of the virus infection for these tissues [46]. A temporary failure of erythropoiesis occurs in virtually all acute Parvovirus infections and can be diagnosed through a reversible disappearance of reticulocytes in peripheral blood [31, 46]. In otherwise healthy patients, erythropoiesis recovers before the patient develops a clinically apparent anaemia. Severe but usually transient aplastic crises are observed in patients with increased erythrocyte turnover due to haemolytic anaemias like spherocytosis, sickle-cell anaemia or thalassaemia [43]. A sustained erythroblastopenia (pure red cell aplasia) is characteristic for patients with inborn or acquired immunodeficiency [28]. Congenital anaemia after transplacental Parvovirus infection appears to be exceptional, only 6 cases have been published to date [37, 47, 48]. Systematic follow-up examinations of larger populations have not observed the complication [45, 49]. Because of the poor outcome of 3 affected children reported in 1994 with 1 fatal course and the other patients remaining transfusion-dependent, an irreversible damage to the erythropoiesis was suspected at that time [37], however, in 3 further cases congenital anaemia was reversible: In 1 case transfusion-dependent anaemia resolved spontaneously at the age of 4 months [50], in 2 other cases it was successfully treated with IVIG [47, 48]. Our own experience with the reported patient supports the beneficial effect of postnatal IVIG treatment and gives one more example for the complete regeneration of haematopoiesis. In 3 of the reported patients erythropoietin has been used to reduce transfusion dependency [37, 48]. It has proven to be ineffective in all these cases. We observed a marked deterioration of the previously mild cholestasis with the reinstitution of erythropoietin treatment at the age of 4 months. The chronological coincidence suggests a deleterious effect due to the stimulation of extramedullary haematopoiesis. Brown et al. reported similar observations confirmed by liver biopsy [37]. We would therefore now clearly advocate against its use. Apart from haematopoietic precursor cells, Parvovirus B19 has been proven to infect foetal cardiac myocytes [51]. Severe anaemia in the hydropic foetus leads to high-output cardiac failure. Intrauterine blood transfusion has repeatedly proven beneficial under these conditions. It has been discussed whether heart failure in foetuses with Parvovirus B19 infection is further aggravated through viral myocarditis. Postnatal echocardiography in our patient however has shown enlargement of all cardiac cavities with moderate tricuspid valve insufficiency but no impairment of myocardial contractility.
Conclusion
▼
Ballantyne syndrome is a variant of preeclampsia with the mandatory clinical features foetal and placental hydrops and maternal anasarca. It is a rare condition only reported in isolated cases so far. Maternal preeclampsia occurs secondary to foetoplacental hydrops, so the key to treatment must be sought in the foetus. Virtually any condition that can cause foetal hydrops can be found as a trigger for Ballantyne syndrome.
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Perigestational Parvovirus B19 infection
While placental hydrops can be clearly identified as the origin of preeclampsia in Ballantyne patients and is at the same time associated with an elevation of maternal sFlt1 and HCG levels, the interrelation of these findings is not yet fully understood and deserves further research. Foetal hydrops caused by a vertical transmission of Parvovirus B19 can lead to stillbirth or preterm delivery. It can be effectively treated by intrauterine blood transfusions and occasionally resolves spontaneously. The experience with our own patient as well as anecdotal reports suggest, that IVIG treatment is effective if foetally acquired parvovirus infection is associated with congenital anaemia. Erythropoietin treatment of anaemia can aggravate cholestasis and is not recommended.
Conflict of Interest
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The authors declare no conflict of interest.
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Schoberer M et al. Ballantyne Syndrome and Congenital … Z Geburtsh Neonatol 2013; 217: 183–188
Ballantyne Syndrome and Congenital Anaemia Associated with Parvovirus B19 Infection: Case Report and Review Ballantyne Syndrom und konnatale Anämie durch Parvovirus B19: Kasuistik und Literaturübersicht M. Schoberer1, A. Rink2, W. Rath2, T. Orlikowsky1 1
Affiliations
2
Key words ▶ Ballantyne syndrome ● ▶ triple edema ● ▶ mirror syndrome ● ▶ preeclampsia ● ▶ fetal hydrops ● ▶ Parvovirus ● ▶ congenital anaemia ● Schlüsselwörter ▶ Ballantyne Syndrom ● ▶ Triple-Ödem ● ▶ Mirror-Syndrom ● ▶ Präeklampsie ● ▶ Hydrops fetalis ● ▶ Parvovirus ● ▶ kongenitale Anämie ●
received accepted after revision
17.04.2012 04.10.2012
Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1355349 Z Geburtsh Neonatol 2013; 217: 183–188 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0948-2393 Correspondence Dr. med. Mark Schoberer Klinik für Kinder- und Jugendmedizin Sektion Neonatologie Pauwelsstrasse 30 52074 Aachen Germany Tel.: + 49/241/803 6117 Fax: + 49/241/808 2436 [email protected]
Klinik für Kinder- und Jugendmedizin, Sektion Neonatologie, Universitätsklinikum Aachen, Aachen, Germany Frauenklinik für Gynäkologie und Geburtshilfe, Universitätsklinikum Aachen, Aachen, Germany
Abstract
Zusammenfassung
Acute maternal Parvovirus B19 infection affects about 1 % of all pregnancies worldwide. Diaplacental transmission of Parvovirus B19 during the second trimester can cause complications like foetal hydrops, premature delivery or foetal loss in about 20–30 % of these pregnancies, whereas the majority of maternal infections remain clinically silent. In individual cases, foetoplacental hydrops (of various origins) can trigger a rare form of Preeclampsia in the pregnant woman. The developing maternal oedema in this situation apparently “mirrors” the hydropic state of the foetus. The symptom triad of foetal hydrops, foetoplacental oedema and maternal anasarca defines Ballantyne syndrome. We report a case of Parvovirus-induced Ballantyne syndrome including a 10-year follow-up of mother and child. While the mother recovered rapidly after (preterm) delivery, the infection complicated the first months of life of the neonate. Congenital transfusion-dependent red cell aplasia and cholestatic hepathopathy took a chronic course but resolved under IVIG treatment. Followup now finds both the former neonate and the mother entirely recovered. Current knowledge on Ballantyne syndrome as well as perigestational Parvovirus infections including congenital anaemia is briefly reported and pathophysiological hypotheses are discussed.
Akute Infektionen mit Parvovirus B19 betreffen weltweit etwa 1 % der Schwangerschaften. Eine diaplazentare Übertragung des Erregers im zweiten Trimenon führt in rund 20–30 % der Fälle zu Komplikationen wie Hydrops Fetalis, Frühgeburtlichkeit oder Spätabort, wohingegen die Mehrzahl der maternalen Infektionen klinisch stumm verläuft. In Einzelfällen kann ein fetoplazentarer Hydrops (egal welchen Ursprungs) bei der Schwangeren eine seltene Form der Präeklampsie auslösen. Maternale Anasarka „spiegeln“ in dieser Situation den Hydrops des Feten. Diese Symptomentrias fetaler Hydrops, Plazentaödem und maternale Anasarka definiert das Ballantyne Syndrom. Wir berichten die Kasuistik eines durch Parvovirus induzierten Ballantyne Syndroms einschließlich einer 10-jährigen Nachbeobachtung von Mutter und Kind. Während sich die Mutter nach der (vorzeitigen) Entbindung rasch erholte, verlief die Infektion bei dem Frühgeborenen langwierig und kompliziert: Sowohl eine kongenitale, transfusionspflichtige aplastische Anämie als auch eine cholestatische Hepatopathie nahmen einen chronischen Verlauf und bildeten sich erst nach rund einem Jahr unter intravenöser Immunglobulintherapie zurück. In der Nachbeobachtung ist die Erkrankung bei Mutter und Kind folgenlos ausgeheilt. Der Artikel gibt eine Übersicht über den aktuellen Stand des Wissens bezüglich des Ballantyne Syndroms und gestationsassoziierter Parvovirus Infektionen. Pathophysiologische Zusammenhänge und Hypothesen werden diskutiert.
Case Report Ballantyne syndrome in a 36-year-old woman
temporal headache, marked oedema, weight gain, proteinuria and arterial hypertension. Blood type (A Rh. pos.) was not indicative for immunological incompatibility.
The 36-year-old gravida 2, para 1 was admitted to our hospital at 26 + 0 weeks of gestation because of suspected preeclampsia with mild
Ballantyne Criteria: The patient had experienced a 17-kg weight gain during pregnancy.
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Schoberer M et al. Ballantyne Syndrome and Congenital … Z Geburtsh Neonatol 2013; 217: 183–188
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Authors
184 Case Report
(230 μmol/L) at the age of 6 months. Hypoproteinaemia and disturbed coagulation tests required ongoing substitution of albumin, fresh frozen plasma and antithrombin. Extrahepatic cholestasis was excluded by hepatobiliary scintigraphy. Erythropoietin was routinely administered as prophylaxis against anaemia of prematurity until the postmenstrual age (PMA) of 36 weeks. A marked aggravation of cholestasis developed after erythropoietin therapy was reinstituted at the age of 4 months in order to reduce transfusion dependency.
IVIG treatment: A first therapeutic trial with intravenously administered immunoglobulins (IVIG) at a dose of 400 mg/kg/d on 5 consecutive days during the third week of life remained ineffective. However, repeated immunoglobulin pulses of 400 mg/kg given monthly from the sixth to tenth month of life proved to be beneficial. Anaemia and cholestasis resolved. Because anaemia recurred after a 3-month trial discontinuation of therapy, immunoglobulin treatment was reinstituted and continued up to the age of 18 months. The patient remains free of symptoms since, although Parvovirus DNA was still detectable at the age of 22 months. 4 months later the Parvovirus PCR examination was negative for the first time and has remained so since.
Hydrops and congenital anaemia followed by cholestatic hepatopathy in the preterm infant The early perinatal period in the newborn was complicated by prematurity (gestational age was 26 completed weeks), hydrops and anaemia. Initial haemoglobin was 46 g/L, haematocrit was 0.13. An immediate red cell transfusion was performed. Parvovirus B19-DNA was isolated by polymerase chain reaction (PCR) from ascites, serum and bone marrow and thus clearly identified as a non-immunological origin of hydrops and anaemia. Echocardiographic examination showed myocardial dilation with preserved contractility.
Fig. 1 Hydropic placenta (diameter 76 mm).
Myelosuppression and congenital anaemia: The patient remained transfusion-dependent for 1 year and received a total of 19 erythrocyte concentrates. A bone-marrow aspirate performed at the age of 3 months displayed the pathognomonic pattern of giant pronormoblasts and the absence of maturing ▶ Fig. 2). Thrombocytopenia was treated erythroid precursors (● by substitution of 9 thrombocyte concentrates in the first 4 weeks of live but thrombopoesis recovered spontaneously thereafter. Hepatopathy: The clinical course became increasingly complicated by the development of a cholestatic hepatopathy. Clinical features were hepatomegaly, ascites and marked jaundice with an elevation of conjugated bilirubin (BC) up to 13.4 mg/dL
Fig. 2 Bone-marrow smear obtained at the age of 3 months: vacuolated giant pronormoblast.
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Daily urine output was diminished to 600 mL, blood pressure rose to 145/90 mmHg. Ultrasound examination revealed placen▶ Fig. 1) and foetal tal hydrops (max. placental diameter: 8 cm, ● ascites as well as pericardial effusions. Proteinuria was 3 g/day, creatinine clearance was reduced to 59 mL/min. Plasma proteins constantly dropped from 52 g/L on admission to 38 g/L in part due to renal wasting but also due to haemodilution. Haemoglobin decreased from 104 g/L on admission to 86 g/L 2 days later, platelet count fell from 109 G/L to 82 G/L in the same period. Serum-hCG exceeded the normal range for the late 2nd term by a 9-fold increase to 904 215 U/L. Maternal blood type (A Rh. pos.) was not indicative for immunological incompatibility. Foetal congestive heart failure and anatomic abnormalities were precluded by foetal ultrasound. Doppler velocimetry demonstrated a flow acceleration in foetal aorta and pulmonary arteries. TORCH screening gave no evidence of an acute infection. Maternal serum was found to be positive for Parvovirus-specific IgG, but negative for IgM, a pattern which was initially interpreted as serostatus after subsided infection. Parvovirus infection was finally proven by polymerase chain reaction (PCR) amplified detection of Parvovirus DNA in maternal serum. The examination had been performed after the virus-genome was isolated from foetal blood and ascites while serial parvovirus IgM examinations in maternal serum had remained negative. 2 days after admission, the progressive preeclampsia and foetal distress with a 5 BPM variability prompted a Caesarean section. Antenatal steroid treatment had been performed with intramuscular betamethasone injections. Renal function in the mother recovered gradually. Oliguria turned into polyuria 3 days after delivery (urine output > 3 L/d). All laboratory test abnormalities fully resolved over the next 2 weeks. Arterial blood pressure normalized under metoprolol treatment. The patient fully recovered from preeclampsia soon after discharge and remains free of symptoms since then.
Case Report 185 Table 1 Overview of published cases of Ballantyne syndrome.
Paternoster et al. Lobato et al. Heyborne et al. Gherman et al. Carbillon et al. Dorman et al. van Selm et al.
Maternal age
Previous
No. of
Reason for
GA at onset of
(years)
pregnancies
foetuses
hydrops
Hydrops (weeks)
37 24 45 28 38
2
singleton singleton twins singleton singleton singleton 3 cases of singletons
idiopathic Rh alloimunisation idiopathic chorioangioma Ebstein anomaly chorioangioma immunological in all cases
28 28 16 25 30
stillbirth
Pt 1: 22 Pt 2: 25 Pt 3: 28
Pt 1: foetal death Pt 2: foetal death Pt 3: foetal death
singleton triplets, one acardius
aneurysm of Galens vein acardius
23
singleton 2 cases of singletons
CMV infection PB 19 infection
29
acardius died under birth. one child survived 13 days, one child discharged healthy death after resuscitation
1 1 4
Pt 1: 39 Pt 2: 24 Pt 3: 29
Pt 1: 4 Pt 2: nn Pt 3: 1
26
none
Rana et al. Proust et al.
29
1
Brochot et al. Hayashi et al.
32 33
none 1
twins
PB 19 infection TTTS
22 25
Vidaeff et al. Midgley et al. Duthie et al.
26 25 34
2 none 1
singleton singleton singleton
idiopathic fetal tachycardia PB 19 infection
31 27
Ordorica et al. Matsubara et al.
Survival 20 days discharged healthy 1 foetocide 16th wk, 1 survivor
foetocide in 36th week* foetal death of donor at 25 2/7, 10 d survival of acceptor discharged healthy discharged healthy discharged healthy
*Due to path. MRI scan after complete reversal of Ballantyne syndrome GA = gestational age; TTTS = twin to twin transfusion syndrome
Long-term-outcome: The patient, now aged 10 years has persistently recovered from the congenital infection: He is free of any residuals and shows excellent performance in psychomotor and somatic development tests as well as above-average school achievement.
Discussion
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Ballantyne syndrome John William Ballantyne first summarized the clinical properties of the syndrome in 1892 [1]. Mandatory features are foetal and placental hydrops in combination with maternal anasarca. “Maternal hydrops syndrome” [2], “pseudotoxemia” [3] and “triple oedema syndrome” [4] are synonymously used terms. The notation “mirror syndrome” [5] indicates that the mother virtually “mirrors” foetal symptoms of severe hydrops. The diagnosis was originally restricted to cases associated with rhesus isoimmunization [6] but has been extended to non-immunological causes since it has become clear that these can likewise induce the triad. Published to date are Ebstein’s anomaly [7], foetal arrhythmias [6], placental chorioangioma [8, 9], aneurysm of Galen’s vein [10], intrauterine infections, e. g., syphilis, cytomegalovirus or human Parvovirus infection [11, 12]. The clinical triad of peripheral oedema, arterial hypertension and proteinuria makes Ballantyne syndrome a variant of preeclampsia. A distinct feature of this variant is a close pathogenetic link to placental hydrops. The large spectrum of possible triggers for foetoplacental hydrops including placental chorioangi▶ Table 1) implies that placental swelling itself rather than oma (● the underlying condition is the original trigger of maternal preeclampsia. Resolution of the foetoplacental oedema whether it occurs spontaneously [13], by intrauterine transfusion [11], elimination of foetal arrhythmias [6] or foetal death of affected multiples [14, 15] results in full restitution of maternal syptoms.
The causative role of hyperplacentation in the genesis of this specific form of preeclampsia however is not fully understood. Glomerular edotheliosis is the pathognomonic renal bioptic finding in preeclampsia, making it the most common glomerular disease in the world [16]. It is characterized by a loss of endothelial fenestrae and by glomerular endothelial swelling with occlusion of the capillary lumen. The absence of endotheliosis in the renal biopsy of one Ballantyne-patient reported by Quagliarello et al. [12] has been interpreted as an indicator to a distinctive pathophysiology of proteinuric hypertension in this group of patients. This view is challenged by the finding, that soluble fmslike tyrosin-kinase (sFlt1) an incomplete circulating VEGF receptor is likewise elevated in Ballyntyne syndrome as in “classical” cases of preeclampsia without hyperplacentation. VEGF deprivation of glomerular endothelial cells caused by the circulating receptor leads to cellular injury and disruption of the filtration apparatus with subsequent proteinuria [16]. The non-haemolytic dilutional anaemia that we observed in our patient is a distinctive feature of Ballantyne syndrome compared to “classical” preeclampsia. The expansion of blood volume results from high maternal serum levels of vasopressin and atrial natriuretic factor [7]. An excess of human chorionic gonadotropin (HCG) appears to be another specific feature of Ballantyne syndrome. The level in our patient exceeded 9 times the anticipated normal value [17]. Colwill et al. reported elevated serum HCG levels in 3 cases of Ballantyne syndrome [18]. In vitro experimentation has identified 3 factors that can influence trophoblastic HCG production: an increased amount of syncytiotrophoblastic cells [19], prolonged states of trophoblastic hypoxaemia [20] and inflammatory cytokines stimulating HCG synthesis [21]. During early pregnancy deficient placental angiogenesis and neovascularization can induce placental ischaemia by an inadequate conversion of the spiral arteries [22]. The syncytiotrophoblast responds to impaired perfusion by increasing the proliferation rate and the amount of secreted HCG [23].
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Autor
186 Case Report
Perigestational Parvovirus B19 infections affect 1 % of pregnancies worldwide [24]. The rate may rise up to 13 % during epidemics, which occur every 4–5 years. Most of the infections follow exposure from the pregnant womens’ own children [25, 26]. Immunoglobulin G seroconversion before conception grants immunity against the infection. It is found in 50–70 % of adult women [24, 25, 27, 28], leaving one third to half of pregnant women susceptible for the infection. If acute Parvovirus infection complicates pregnancy, vertical transmission rates are estimated to be 30–50 % [26, 28, 29] or may be even higher [30]. Intrauterine Parvovirus B19 infection can cause spontaneous abortion [24], especially during the first trimester [29, 31]. Stillbirth without hydrops occurs mainly from the late second trimester to term and may account for up to 15 % of all cases of foetal deaths [27]. Parvovirus is known to cause non-immunological foetal hydrops since 1984 [32] and has been observed in 18 % of such cases [33]. Hydrops is a typical complication of vertical transmission during the second trimester [28, 29, 34]. While affected individuals may experience severe complications, the overall risk of a clinically overt disease appears to be rare, even after vertical transmission. Miller et al. report a 9 % risk of foetal loss in a prospective cohort study of 427 pregnant women with confirmed B19 infection [34]. The spontaneous resolution of hydrops and the following delivery of symptomfree newborns at term have been repeatedly reported, especially after intrauterine red cell transfusion [35, 36]. Long-term sequelae in surviving children have been rarely observed in large follow-up studies [29, 34, 37]. Therefore termination of affected pregnancies cannot be routinely advocated. Management plans for pregnant women after Parvovirus exposition or serologically proven infection draw on identification of the source of exposure, maternal serological testing and targeted foetal ultrasound examinations for 6–14 weeks after exposure [35, 38, 39]. Inrauterine blood transfusions play the essential role in the management of (anaemia related) foetal hydrops and have been proven to improve survival [6, 40–42] Little information exists regarding the benefits of maternal IVIG treatment if acute Parvovirus infection occurs during pregnancy. Nevertheless such an approach has been advocated [43]. Matsuda et al. reported the successful treatment of foetal hydrops by injection of a B19-IgGrich immunoglobulin into the foetal peritoneal cavity [44]. Immunologically mediated foetal haemolysis usually causes hydrops only when haematocrit values fall short of 0.15 L/L. Foetal Parvovirus infection in contrast can trigger hydrops even in the presence of only mild anaemia, especially if myocardial affection triggers congestive heart failure. Only few data have been published regarding the long-term outcome of children affected by parvovirus-induced foetal hydrops. Nagel et al. report a 6-months to 8-years follow-up of 16 survivors. They report a delay of psychomotor development in 5 of these children, 3 of them with mild and 2 with severe degrees [45]. It is most likely that such mental impairment is not attributable to the foetal infection itself but its secondary complications hydrops, anaemia and prematuritiy. Rodis et al. found no differences in psychomotor development between 108 survivors of pregnancies complicated by serologically proven new-onset Parvovirus infection as compared to 93 controls in whom maternal serostatus confirmed past infection [46].
Congenital anaemia induced by intrauterine Parvovirus B19 infection Globoside, a neutral glycoprotein, acts as cellular receptor in Parvovirus infections. It is mainly expressed on erythroid precursor cells but is also found on thrombopoetic and myeloic precursors, as well as placental cells and foetal myocardial cells. Clinical and histopathological findings confirm the strong tropism of the virus infection for these tissues [46]. A temporary failure of erythropoiesis occurs in virtually all acute Parvovirus infections and can be diagnosed through a reversible disappearance of reticulocytes in peripheral blood [31, 46]. In otherwise healthy patients, erythropoiesis recovers before the patient develops a clinically apparent anaemia. Severe but usually transient aplastic crises are observed in patients with increased erythrocyte turnover due to haemolytic anaemias like spherocytosis, sickle-cell anaemia or thalassaemia [43]. A sustained erythroblastopenia (pure red cell aplasia) is characteristic for patients with inborn or acquired immunodeficiency [28]. Congenital anaemia after transplacental Parvovirus infection appears to be exceptional, only 6 cases have been published to date [37, 47, 48]. Systematic follow-up examinations of larger populations have not observed the complication [45, 49]. Because of the poor outcome of 3 affected children reported in 1994 with 1 fatal course and the other patients remaining transfusion-dependent, an irreversible damage to the erythropoiesis was suspected at that time [37], however, in 3 further cases congenital anaemia was reversible: In 1 case transfusion-dependent anaemia resolved spontaneously at the age of 4 months [50], in 2 other cases it was successfully treated with IVIG [47, 48]. Our own experience with the reported patient supports the beneficial effect of postnatal IVIG treatment and gives one more example for the complete regeneration of haematopoiesis. In 3 of the reported patients erythropoietin has been used to reduce transfusion dependency [37, 48]. It has proven to be ineffective in all these cases. We observed a marked deterioration of the previously mild cholestasis with the reinstitution of erythropoietin treatment at the age of 4 months. The chronological coincidence suggests a deleterious effect due to the stimulation of extramedullary haematopoiesis. Brown et al. reported similar observations confirmed by liver biopsy [37]. We would therefore now clearly advocate against its use. Apart from haematopoietic precursor cells, Parvovirus B19 has been proven to infect foetal cardiac myocytes [51]. Severe anaemia in the hydropic foetus leads to high-output cardiac failure. Intrauterine blood transfusion has repeatedly proven beneficial under these conditions. It has been discussed whether heart failure in foetuses with Parvovirus B19 infection is further aggravated through viral myocarditis. Postnatal echocardiography in our patient however has shown enlargement of all cardiac cavities with moderate tricuspid valve insufficiency but no impairment of myocardial contractility.
Conclusion
▼
Ballantyne syndrome is a variant of preeclampsia with the mandatory clinical features foetal and placental hydrops and maternal anasarca. It is a rare condition only reported in isolated cases so far. Maternal preeclampsia occurs secondary to foetoplacental hydrops, so the key to treatment must be sought in the foetus. Virtually any condition that can cause foetal hydrops can be found as a trigger for Ballantyne syndrome.
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Perigestational Parvovirus B19 infection
While placental hydrops can be clearly identified as the origin of preeclampsia in Ballantyne patients and is at the same time associated with an elevation of maternal sFlt1 and HCG levels, the interrelation of these findings is not yet fully understood and deserves further research. Foetal hydrops caused by a vertical transmission of Parvovirus B19 can lead to stillbirth or preterm delivery. It can be effectively treated by intrauterine blood transfusions and occasionally resolves spontaneously. The experience with our own patient as well as anecdotal reports suggest, that IVIG treatment is effective if foetally acquired parvovirus infection is associated with congenital anaemia. Erythropoietin treatment of anaemia can aggravate cholestasis and is not recommended.
Conflict of Interest
▼
The authors declare no conflict of interest.
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