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DOI: 10.1542/peds.2009-3490; originally published online July 5, 2010;2010;126;e483PediatricsJane McDougall

Luregn Jan Schlapbach, Thomas Riedel, Vera Genitsch, Mathias Nelle and Felicity

Transfusion SyndromeFatal Pulmonary Embolism in a Premature Neonate After Twin-to-Twin

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Fatal Pulmonary Embolism in a Premature Neonate

After Twin-to-Twin Transfusion Syndrome

abstractThrombotic events are being increasingly recognized during the neo-

natal 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 in-

creased, 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 un-

derdiagnosed and that additional studies are needed to define infants

at risk and optimal treatment strategies. Pediatrics 2010;126:

e483e487

AUTHORS:Luregn Jan Schlapbach, MD,a Thomas Riedel,

MD,a Vera Genitsch, MD,b Mathias Nelle, MD,a and Felicity

Jane McDougall, MDa

Departments ofaPediatrics andbPathology, 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: [email protected]

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 financial relationships relevant to this article to disclose.

CASE REPORTS

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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 underdiag-

nosed.2 The incidence of thromboem-bolic events in children is highest dur-

ing the neonatal period,3 which is

characterized by a delicate equilib-

rium of procoagulant versus anticoag-

ulant factors. We present here the

case of a premature newborn with

fatal PE.

CASE REPORT

A premature girl weighing 1400 g was

born at 29 weeks gestational age bycesarean 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 dis-

tress syndrome, and umbilical venous

and arterial catheters were placed.

The umbilical artery catheter was im-

mediately removed, because the tipwas malpositioned in the iliac vessels.

Blood counts on admission revealed

borderline polycythemia (hemoglobin:

202 g/L; hematocrit: 58%) and a nor-

mal platelet count (320 109/L). After

receiving porcine surfactant (Curo-

surf) for radiologically evident hyaline

membrane disease, the infant was ex-

tubated and did well on room air with-

out respiratory assistance. The umbil-

ical venous catheter was removed onday 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 inter-

preted as an early manifestation of

bronchopulmonary dysplasia (Fig 1).

Therefore, diuretic therapy with spi-

ronolactone and hydrochlorothiazide

was initiated, but no clear improve-

ment was seen. Arterial blood pres-

sure and electrolyte (including cal-

cium) levels were always within

normal ranges. On day 14 of life, di-

rectly after capillary heel-stick blood

sampling, her right ipsilateral leg be-

came pale and cooler, and no periph-

eral pulses were palpable. The infant

was otherwise well and showed no

other signs of compromised perfu-

sion. Within an hour, the perfusion of

the right leg normalized spontane-

ously. Duplex sonography of the ab-

dominal and lower extremity vessels,

performed by an experienced pediat-

ric radiologist, excluded arterial or ve-

nous thromboses, including renal vein

thrombosis (RVT). To rule out a cardiac

thromboembolic origin, echocardiog-

raphy was performed; the results

were normal, without any evidence ofcongenital heart disease or pulmonary

hypertension. Given the rapid sponta-

neous resolution and normal radio-

graphic findings, arterial vasospasm

triggered by the painful stimulus was

diagnosed.

On day 20, while lying comfortably in

bed, the infant became acutely cya-

notic (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 thoraco-

centesis to rule out tension pneumo-

thorax did not yield air and did not

improve her clinical status. On the

radiograph, diminished pulmonary

vasculature was noted. Echocardiog-

raphy showed suprasystemic pulmo-

nary arterial pressure with severe

tricuspid regurgitation, flattened

ventricular septum with almost no

flow across the pulmonary arteries,

right-to-left shunting across the fo-

ramen ovale, and right-sided ventric-

ular dilatation. Laboratory studies

revealed thrombocytopenia (122

109/L) and severe lactic acidosis (pH6.8; lactate: 14.8 mmol/L). Extracor-

poreal membrane oxygenation was

not considered because of the pre-

maturity and size of the infant. De-

spite maximal intensive care support

with catecholamines, high-frequency

oscillation ventilation, and inhalative

nitric oxide, the infant further deteri-

orated and died 2 hours after the

sudden event.

FIGURE 1

Chest radiograph on day 10 showing increased pulmonary markenings.

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At autopsy, large emboli were found

extending into the left and right pulmo-

nary 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 exten-sively calcified RVTs (Fig 5). Because of

the high degree of calcification and

signs of beginning thrombus organiza-

tion, the age of the RVT was estimated

to be1 week, in contrast to the more

recent smaller pulmonary artery em-

bolisms estimated to be aged several

days. A renal origin of the PEs was

thought to be probable.

Family history revealed that the mater-

nal grandfather had experienced a PEat the age of 78 years; otherwise, no

thrombotic events were reported. An

extensive thrombophilia screening

was performed on the deceased in-

fant, her surviving monozygotic twin

sister, and the parents. Results of co-

agulation studies including tests for

protein C and S levels, antithrombin III,

homocysteine concentration, and an-

tiphospholipid antibodies were nega-

tive. Results of genetic screeningfor factor V Leiden (R506Q) and pro-

thrombin mutation (20210G3A) and

methylene-tetrahydrofolate reductase

variant (C677T) were negative.

The surviving twin (birth weight:

1245 g; hemoglobin: 112 g/L; and he-

matocrit: 33% at admission), apart

from intubation and ventilation for hy-

aline membrane disease, had an un-

eventful course. Results of echocardi-

ography and renal Doppler studies andher urinary status were normal.

DISCUSSION

To the best of our knowledge, this is

the first case report of a fatal PE in a

premature infant. In the absence of in-

herited thrombophilia and dissemi-

nated intravascular coagulation, the

extensive renal and pulmonary throm-

boses were thought to have arisen ei-

ther in relation to the umbilical venous

catheter or as an indirect conse-

quence of TTTS. We assume that the

combination of polycythemia, prema-

turity, 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 Ac-

cordingly, TTTS was shown to be an in-

dependent risk factor in a study on

neonatal ischemic stroke.5

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).

CASE REPORTS



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In contrast to adults, in whom PE rep-

resents a frequent cardiovascular

emergency, the condition is exceed-

ingly 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

true incidence of PE is probably under-

estimated. For neonates, several case

reports on PE have been published,611

describing term infants with presenta-

tions that ranged from mild respira-

tory distress to severe hypoxemia.

Therapeutic options include thrombol-

ysis, percutaneous catheter-based em-

bolectomy, and open surgical embo-

lectomy.6,10,12 Diagnosis of PE in infants

is difficult, because experience with

ventilation-perfusion lung scanning

and spiral computed tomography is

limited in this age group, andpulmonary angiography is invasive.10

Consequently, most cases are diag-

nosed either by echocardiography or

during the postmortem examina-

tion.9,13 Smaller PEs frequently may be

missed or misinterpreted as respira-

tory diseases such as pulmonary

infection or lung edema. In our case,

moderate hypoxemia caused retro-

spectively by smaller PEs was mis-

taken as bronchopulmonary dysplasia.Failure to correctly diagnose PE may

lead to severe pulmonary hyperten-

sion, right-sided heart failure, and

death, as in our case. PE needs to be

distinguished from pulmonary mi-

crothrombi syndrome, which may

cause severe pulmonary hyperten-

sion in neonates but is not associ-

ated with larger vessel embolism.14

RVT is the most common non

catheter-related thrombosis in neo-nates, occurring in 0.5 of 1000 NICU ad-

missions.2,3 Classic symptoms are

hematuria, palpable abdominal mass,

thrombocytopenia, and, frequently, ar-

terial hypertension, but only a minority

of patients present the complete tri-

ad.15 Although Doppler ultrasound

studies are commonly used to diag-

nose RVT, classic signs such as absent

venous or reversed diastolic arterial

flow may be unreliable with neonatalkidneys 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 echocar-

diography when compared with con-

trast venography to detect catheter-

associated thrombus formation was

relatively poor with positive and nega-

tive predictive values of 43% to 60%

FIGURE 4

Postmortem histology of the pulmonary vascular bed showing a pulmonary embolus (arrow).

FIGURE 5

Postmortem histology of the kidney showing a calcified RVT (arrow).

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and 73% to 76%, respectively.17 How-

ever, given the practicality and lack of

adverse effects of Doppler ultrasound

in comparison to venography and MRI,

Doppler ultrasound currently repre-

sents the method of choice for diag-

nosing RVT.18,19 The finding 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 pu-

berty and adolescence.20 Sepsis or ne-

crotizing enterocolitis, hypovolemia,

maternal diabetes, asphyxia, congeni-

tal heart disease, and central venous

catheters represent the most frequent

clinical risk factors in neonates.2 Al-

though vitamin K dependent proco-

agulant clotting factors are decreased

in neonates, particularly if they are

born preterm, coagulation-inhibitor

concentrations are significantly lower

compared with those of adultsas well.3In addition, the activity of both proco-

agulant and anticoagulant factors un-

dergoes significant changes during

the neonatal period. This delicate equi-

librium between coagulation and fibri-

nolysis is easily disturbed by perina-

tal or iatrogenic conditions. In our

case, no inherited cause of thrombo-

philia was found. A recent meta-

analysis by Young et al20 revealed

that inherited deficienc ies of the na t-ural anticoagulants protein C, pro-

tein S, and antit hrombin 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 in-

fants with sudden deterioration of ox-

ygenation, acute signs of respiratory

distress, or unexplained pulmonary

hypertension.

ACKNOWLEDGMENTS

We thank Manuela Albisetti, MD (De-partment of Hematology, University

Childrens Hospital Zurich, Zurich,

Switzerland) for critical comments

and review of the manuscript.

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 thromboem-

bolic emergencies. Semin Fetal Neonatal

Med.2006;11(3):198206

4. Lopriore E, Oepkes D. Fetal and neonatal

haematological complications in monocho-

rionic 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 pret erm infa nt. Stroke.

2007;38(6):17591765

6. DeBlancheLE, Schmitz ML,JohnsonCE, Best

TH, Drummond-Webb JJ. Successful surgi-

cal management of a neonate with a saddle

pulmonary embolus. Ann Thorac Surg.

2004;78(1):e1e2

7. Goble MM, Gomez CA. Neonatal pulmonary

artery thrombosis: echocardiographic

characteristics and possible contributing

factors.J Am Soc Echocardiogr.2005;18(6):

693

8. Kenny D, Tsai-Goodman B. Neonatal arterial

thrombus mimicking congenital heart dis-

ease. ArchDis Child Fetal Neonatal Ed. 2007;

92(1):F59F61

9. Allred L, Ruiz R, Jones D, Donn SM. Intracta-

ble 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):520522

11. Biss TT, Brandao LR, Kahr WH, Chan AK, Wil-

liams 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. Anti-

th ro mb ot ic th er ap y in ne on at es an d

children: American College of Chest Physi-cians Evidence-Based Clinical Practice

Guidelines (8th Edition). Chest. 2008;133(6

suppl):887S968S

13. Champ C, Byard RW. Pulmonary thrombo-

embolism and unexpected death in infancy.

J Paediatr Child Health. 1994;30(6):550551

14. Levin DL, Weinberg AG, Perkin RM. Pulmo-

nary microthrombi syndrome in newborn

infants with unresponsive persistent pul-

monary hypertension. J Pediatr. 1983;

102(2):299 303

15. Lau KK, Stoffman JM, Williams S, et al; Cana-

dian 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):413418

17. Roy M, Turner-Gomes S, Gill G, Way C, Mer-

nagh J, Schmidt B. Accuracy of Doppler

echocardiography for the diagnosis of

thrombosis associated with umbilical ve-

nous catheters. J Pediatr. 2002;140(1):

131134

18. Hibbert J, Howlett DC, Greenwood KL, Mac-

DonaldLM, Saunders AJ.The ultrasound ap-

pearances of neonatal renal vein thrombo-

sis.Br J Radiol. 1997;70(839):1191119419. Argyropoulou MI, Giapros VI, Papadopoulou

F, et al. Renal venous thrombosis in an in-

fant with predisposing thrombotic factors:

color Doppler ultrasound and MR evalua-

tion.Eur Radiol. 2003;13(8):20272030

20. Young G, Albisetti M, Bonduel M, et al. Im-

pact of inherited thrombophilia on venous

thromb oemboli sm in child ren: a system-

atic review and meta-analysis of observa-

tiona l studi es. Circulation. 2008;118(13):

13731382

CASE REPORTS



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DOI: 10.1542/peds.2009-3490; originally published online July 5, 2010;2010;126;e483Pediatrics

Jane McDougallLuregn Jan Schlapbach, Thomas Riedel, Vera Genitsch, Mathias Nelle and Felicity

Transfusion SyndromeFatal Pulmonary Embolism in a Premature Neonate After Twin-to-Twin

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