Fatal Pulmonary Embolism in a Premature Neonate After Twin-to-Twin Transfusion Syndrome Luregn Jan Schlapbach, Thomas Riedel, Vera

Genitsch, Mathias Nelle and Felicity Jane McDougall Pediatrics 2010;126;e483; originally published online July 5, 2010; DOI: 10.1542/peds.2009-3490

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2010 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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CASE REPORTS

Fatal Pulmonary Embolism in a Premature Neonate After Twin-to-Twin Transfusion Syndrome

AUTHORS: Luregn Jan Schlapbach, MD,a Thomas Riedel, MD,a Vera Genitsch, MD,b Mathias Nelle, MD,a and Felicity Jane McDougall, MDa
Departments of aPediatrics and bPathology, University of Berne, Berne, Switzerland KEY WORDS twin-twin transfusion, pulmonary embolism, premature infant, renal vein thrombosis ABBREVIATIONS PEpulmonary embolism TTTStwin-to-twin transfusion syndrome RVTrenal vein thrombosis www.pediatrics.org/cgi/doi/10.1542/peds.2009-3490 doi:10.1542/peds.2009-3490 Accepted for publication Apr 26, 2010 Address correspondence to Luregn Jan Schlapbach, MD, Department of Pediatrics, Inselspital, University of Bern, 3010 Bern, Switzerland. E-mail: luregn.schlapbach@insel.ch PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2010 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to this article to disclose.

abstract
Thrombotic events are being increasingly recognized during the neonatal period. An infant girl was born at 29 weeks gestation after a pregnancy complicated by twin-to-twin transfusion syndrome. After an initial uncomplicated clinical course, her oxygen requirement increased, which was interpreted as an early sign of bronchopulmonary dysplasia. At 3 weeks of age, she suddenly collapsed and died of severe pulmonary hypertension. At autopsy, multiple pulmonary artery emboli and several older renal vein thromboses were found. Results of genetic analyses of the infant and her family were negative for thrombophilia. Although embolism represents a frequent emergency in adults, fatal pulmonary embolism has never, to our knowledge, been described for premature infants. This case suggests that thrombotic events are underdiagnosed and that additional studies are needed to dene infants at risk and optimal treatment strategies. Pediatrics 2010;126: e483e487

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Although pulmonary embolism (PE) represents a frequent emergency in adults, PE occurs exceedingly rarely in the pediatric age group.1 However, it is increasingly being recognized that thrombotic disease may be underdiagnosed.2 The incidence of thromboembolic events in children is highest during the neonatal period,3 which is characterized by a delicate equilibrium of procoagulant versus anticoagulant factors. We present here the case of a premature newborn with fatal PE.
FIGURE 1

CASE REPORT
A premature girl weighing 1400 g was born at 29 weeks gestational age by cesarean delivery because of maternal chorioamnionitis. The monozygotic twin pregnancy had been complicated by twin-to-twin transfusion syndrome (TTTS); the surviving infant (presented here) was the recipient. The infant was intubated because of respiratory distress syndrome, and umbilical venous and arterial catheters were placed. The umbilical artery catheter was immediately removed, because the tip was malpositioned in the iliac vessels. Blood counts on admission revealed borderline polycythemia (hemoglobin: 202 g/L; hematocrit: 58%) and a normal platelet count (320 109/L). After receiving porcine surfactant (Curosurf) for radiologically evident hyaline membrane disease, the infant was extubated and did well on room air without respiratory assistance. The umbilical venous catheter was removed on day 3, and peripheral intravenous catheters were removed on day 9 when full enteral feeds were reached. On day 10, the infant started requiring 25% to 30% supplemental oxygen. Radiologically, patchy pulmonary markenings were noted and interpreted as an early manifestation of bronchopulmonary dysplasia (Fig 1). Therefore, diuretic therapy with spie484 SCHLAPBACH et al

Chest radiograph on day 10 showing increased pulmonary markenings.

ronolactone and hydrochlorothiazide was initiated, but no clear improvement was seen. Arterial blood pressure and electrolyte (including calcium) levels were always within normal ranges. On day 14 of life, directly after capillary heel-stick blood sampling, her right ipsilateral leg became pale and cooler, and no peripheral pulses were palpable. The infant was otherwise well and showed no other signs of compromised perfusion. Within an hour, the perfusion of the right leg normalized spontaneously. Duplex sonography of the abdominal and lower extremity vessels, performed by an experienced pediatric radiologist, excluded arterial or venous thromboses, including renal vein thrombosis (RVT). To rule out a cardiac thromboembolic origin, echocardiography was performed; the results were normal, without any evidence of congenital heart disease or pulmonary hypertension. Given the rapid spontaneous resolution and normal radiographic ndings, arterial vasospasm triggered by the painful stimulus was diagnosed. On day 20, while lying comfortably in bed, the infant became acutely cyanotic (oxygen saturation: 60%) and manifested respiratory distress with

tachypnea and subcostal retractions. Her blood pressure was 42/22 mm Hg (mean: 30 mm Hg), and her pulse was 184 beats per minute. Because no improvement in oxygenation was achieved under 100% oxygen, she was intubated and mechanically ventilated. Emergency bilateral needle thoracocentesis to rule out tension pneumothorax did not yield air and did not improve her clinical status. On the radiograph, diminished pulmonary vasculature was noted. Echocardiography showed suprasystemic pulmonary arterial pressure with severe tricuspid regurgitation, attened ventricular septum with almost no ow across the pulmonary arteries, right-to-left shunting across the foramen ovale, and right-sided ventricular dilatation. Laboratory studies revealed thrombocytopenia (122 109/L) and severe lactic acidosis (pH 6.8; lactate: 14.8 mmol/L). Extracorporeal membrane oxygenation was not considered because of the prematurity and size of the infant. Despite maximal intensive care support with catecholamines, high-frequency oscillation ventilation, and inhalative nitric oxide, the infant further deteriorated and died 2 hours after the sudden event.

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At autopsy, large emboli were found extending into the left and right pulmonary artery (Fig 2). The right lower lobe showed a large area of infarction (Fig 3). Microscopic examination revealed multiple peripheral pulmonary artery embolisms (Fig 4) and several extensively calcied RVTs (Fig 5). Because of the high degree of calcication and signs of beginning thrombus organization, the age of the RVT was estimated to be 1 week, in contrast to the more recent smaller pulmonary artery embolisms estimated to be aged several days. A renal origin of the PEs was thought to be probable. Family history revealed that the maternal grandfather had experienced a PE at the age of 78 years; otherwise, no thrombotic events were reported. An extensive thrombophilia screening was performed on the deceased infant, her surviving monozygotic twin sister, and the parents. Results of coagulation studies including tests for protein C and S levels, antithrombin III, homocysteine concentration, and antiphospholipid antibodies were negative. Results of genetic screening for factor V Leiden (R506Q) and prothrombin mutation (20210G3 A) and methylene-tetrahydrofolate reductase variant (C677T) were negative. The surviving twin (birth weight: 1245 g; hemoglobin: 112 g/L; and hematocrit: 33% at admission), apart from intubation and ventilation for hyaline membrane disease, had an uneventful course. Results of echocardiography and renal Doppler studies and her urinary status were normal.

FIGURE 2
Postmortem specimen of the right lung with opened main pulmonary artery showing a large embolus (arrow).

FIGURE 3
Postmortem specimen showing bilateral pulmonary emboli (arrow) and infarction in the right lower lobe (arrow).

DISCUSSION
To the best of our knowledge, this is the rst case report of a fatal PE in a premature infant. In the absence of inherited thrombophilia and disseminated intravascular coagulation, the extensive renal and pulmonary thromboses were thought to have arisen eiPEDIATRICS Volume 126, Number 2, August 2010

ther in relation to the umbilical venous catheter or as an indirect consequence of TTTS. We assume that the combination of polycythemia, prematurity, and triggers such as diminished intravascular volume under diuretics may have further propagated the fatal

thrombotic events. Recipient twins may be at particular risk because of chronic hyperviscosity associated with polycythemia and thrombocytosis.4 Accordingly, TTTS was shown to be an independent risk factor in a study on neonatal ischemic stroke.5
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FIGURE 4
Postmortem histology of the pulmonary vascular bed showing a pulmonary embolus (arrow).

ysis, percutaneous catheter-based embolectomy, and open surgical embolectomy.6,10,12 Diagnosis of PE in infants is difcult, because experience with ventilation-perfusion lung scanning and spiral computed tomography is limited in this age group, and pulmonary angiography is invasive.10 Consequently, most cases are diagnosed either by echocardiography or during the postmortem examination.9,13 Smaller PEs frequently may be missed or misinterpreted as respiratory diseases such as pulmonary infection or lung edema. In our case, moderate hypoxemia caused retrospectively by smaller PEs was mistaken as bronchopulmonary dysplasia. Failure to correctly diagnose PE may lead to severe pulmonary hypertension, right-sided heart failure, and death, as in our case. PE needs to be distinguished from pulmonary microthrombi syndrome, which may cause severe pulmonary hypertension in neonates but is not associated with larger vessel embolism.14 RVT is the most common non catheter-related thrombosis in neonates, occurring in 0.5 of 1000 NICU admissions.2,3 Classic symptoms are hematuria, palpable abdominal mass, thrombocytopenia, and, frequently, arterial hypertension, but only a minority of patients present the complete triad.15 Although Doppler ultrasound studies are commonly used to diagnose RVT, classic signs such as absent venous or reversed diastolic arterial ow may be unreliable with neonatal kidneys because of clot retraction and collateral venous perfusion.15,16 It should be noted that, in a study on 47 neonates with central catheters, the accuracy of Doppler echocardiography when compared with contrast venography to detect catheterassociated thrombus formation was relatively poor with positive and negative predictive values of 43% to 60%

FIGURE 5
Postmortem histology of the kidney showing a calcied RVT (arrow).

In contrast to adults, in whom PE represents a frequent cardiovascular emergency, the condition is exceedingly rare in children. A prospective Dutch registry of children aged 0 to 18 years has revealed an incidence of 0.14 per 10 0000 children.1 However, the
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true incidence of PE is probably underestimated. For neonates, several case reports on PE have been published,611 describing term infants with presentations that ranged from mild respiratory distress to severe hypoxemia. Therapeutic options include thrombol-

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CASE REPORTS

and 73% to 76%, respectively.17 However, given the practicality and lack of adverse effects of Doppler ultrasound in comparison to venography and MRI, Doppler ultrasound currently represents the method of choice for diagnosing RVT.18,19 The nding of older RVT in our patient after death, which was undetected by Doppler sonography, is worrisome and suggests that RVT may be underdiagnosed. Within the entire pediatric population, neonates are at the greatest risk for venous thromboembolism (5.1 in 100 000 live births per year), with a second peak in incidence during puberty and adolescence.20 Sepsis or necrotizing enterocolitis, hypovolemia, maternal diabetes, asphyxia, congenital heart disease, and central venous catheters represent the most frequent REFERENCES
1. Van Ommen CH, Peters M. Acute pulmonary embolism in childhood. Thromb Res. 2006; 118(1):1325 2. Saracco P, Parodi E, Fabris C, Cecinati V, Molinari AC, Giordano P. Management and investigation of neonatal thromboembolic events: genetic and acquired risk factors. Thromb Res. 2009;123(6):805 809 3. Thornburg C, Pipe S. Neonatal thromboembolic emergencies. Semin Fetal Neonatal Med. 2006;11(3):198 206 4. Lopriore E, Oepkes D. Fetal and neonatal haematological complications in monochorionic twins. Semin Fetal Neonatal Med. 2008;13(4):231238 5. Benders MJ, Groenendaal F, Uiterwaal CS, et al. Maternal and infant characteristics associated with perinatal arterial stroke in the preterm infant. Stroke. 2007;38(6): 1759 1765 6. De Blanche LE, Schmitz ML, Johnson CE, Best TH, Drummond-Webb JJ. Successful surgical management of a neonate with a saddle pulmonary embolus. Ann Thorac Surg. 2004;78(1):e1 e2 7. Goble MM, Gomez CA. Neonatal pulmonary artery thrombosis: echocardiographic characteristics and possible contributing factors. J Am Soc Echocardiogr. 2005;18(6): 693

clinical risk factors in neonates.2 Although vitamin K dependent procoagulant clotting factors are decreased in neonates, particularly if they are born preterm, coagulation-inhibitor concentrations are signicantly lower compared with those of adults as well.3 In addition, the activity of both procoagulant and anticoagulant factors undergoes signicant changes during the neonatal period. This delicate equilibrium between coagulation and brinolysis is easily disturbed by perinatal or iatrogenic conditions. In our case, no inherited cause of thrombophilia was found. A recent metaanalysis by Young et al20 revealed that inherited deciencies of the natural anticoagulants protein C, protein S, and antithrombin are present in 10% of pediatric patients with venous thromboembolism.

CONCLUSIONS
Our case illustrates that both renal and smaller pulmonary thromboses may progress asymptomatically; therefore, the incidence of PE and RVT may be underestimated. Considering the potentially lethal complications of PE, pediatricians and neonatologists should maintain a high degree of suspicion for thrombotic events in infants with sudden deterioration of oxygenation, acute signs of respiratory distress, or unexplained pulmonary hypertension.

ACKNOWLEDGMENTS We thank Manuela Albisetti, MD (Department of Hematology, University Childrens Hospital Zurich, Zurich, Switzerland) for critical comments and review of the manuscript.

8. Kenny D, Tsai-Goodman B. Neonatal arterial thrombus mimicking congenital heart disease. Arch Dis Child Fetal Neonatal Ed. 2007; 92(1):F59 F61 9. Allred L, Ruiz R, Jones D, Donn SM. Intractable respiratory failure in a term newborn. Am J Perinatol. 2008;25(2):101103 10. Sawyer T, Antle A, Studer M, Thompson M, Perry S, Mahnke CB. Neonatal pulmonary artery thrombosis presenting as persistent pulmonary hypertension of the newborn. Pediatr Cardiol. 2009;30(4):520 522 11. Biss TT, Brandao LR, Kahr WH, Chan AK, Williams S. Clinical features and outcome of pulmonary embolism in children. Br J Haematol. 2008;142(5):808 818 12. Monagle P, Chalmers E, Chan A, et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 suppl):887S968S 13. Champ C, Byard RW. Pulmonary thromboembolism and unexpected death in infancy. J Paediatr Child Health. 1994;30(6):550 551 14. Levin DL, Weinberg AG, Perkin RM. Pulmonary microthrombi syndrome in newborn infants with unresponsive persistent pulmonary hypertension. J Pediatr. 1983; 102(2):299 303

15. Lau KK, Stoffman JM, Williams S, et al; Canadian Pediatric Thrombosis and Hemostasis Network. Neonatal renal vein thrombosis: review of the English-language literature between 1992 and 2006. Pediatrics. 2007; 120(5). Available at: www.pediatrics.org/ cgi/content/full/120/5/e1278 16. Elsaify WM. Neonatal renal vein thrombosis: grey-scale and Doppler ultrasonic features. Abdom Imaging. 2009;34(3):413 418 17. Roy M, Turner-Gomes S, Gill G, Way C, Mernagh J, Schmidt B. Accuracy of Doppler echocardiography for the diagnosis of thrombosis associated with umbilical venous catheters. J Pediatr. 2002;140(1): 131134 18. Hibbert J, Howlett DC, Greenwood KL, MacDonald LM, Saunders AJ. The ultrasound appearances of neonatal renal vein thrombosis. Br J Radiol. 1997;70(839):11911194 19. Argyropoulou MI, Giapros VI, Papadopoulou F, et al. Renal venous thrombosis in an infant with predisposing thrombotic factors: color Doppler ultrasound and MR evaluation. Eur Radiol. 2003;13(8):20272030 20. Young G, Albisetti M, Bonduel M, et al. Impact of inherited thrombophilia on venous thromboembolism in children: a systematic review and meta-analysis of observational studies. Circulation. 2008;118(13): 13731382

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Fatal Pulmonary Embolism in a Premature Neonate After Twin-to-Twin Transfusion Syndrome Luregn Jan Schlapbach, Thomas Riedel, Vera Genitsch, Mathias Nelle and Felicity Jane McDougall Pediatrics 2010;126;e483; originally published online July 5, 2010; DOI: 10.1542/peds.2009-3490
Updated Information & Services References including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/126/2/e483.full.h tml This article cites 19 articles, 5 of which can be accessed free at: http://pediatrics.aappublications.org/content/126/2/e483.full.h tml#ref-list-1 Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xht ml Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2010 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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