An interesting presentation in an infant of a diabetic mother

1. An interesting presentation in an infant of a diabetic mother

2. History • Baby SB, male infant • Born 3 December 2009 at Bedford Gardens Hospital, JHB • Caesarean section – difficult delivery anticipated • Mother 41 years old, first pregnancy • Gestational diabetes, treated with Glucophage. • Not optimally controlled – HbA1c levels after delivery 7.9%. Estimated average glucose – 10.0mmol/l • Excessive weight gain in past week – oedema. Reportedly not hypertensive. Mother’s weight 143kg. Blood pressure at delivery 220/140mmHg • Gestational age 36 weeks. Mother received 2 doses steroids • Delivery not particularly difficult – no obvious trauma to baby • Apgar score 9/10 at 1 minute, 9/10 at 5 minutes

3. Initial Clinical Findings • Large-for-gestational-age baby • Weight 5.3kg, head circumference 38cm, length 54cm • Not dysmorphic • Not obviously plethoric • Mild-moderate respiratory distress • Admitted to neonatal ICU for oxygen and blood-glucose monitoring • Initial blood glucose 1.7mmol/l

4. While admitting and examining baby, noted to have bluish right arm, with poor perfusion and capillary refill • NB: no procedures (arterial) had been performed on this arm • Clear line of demarcation became evident, high up on right arm. Arm/hand not atrophic • Chest – clear • Cardiovascular system • normal heart sounds, no murmurs audible • Pulses present in lower limbs and left arm, but no right brachial/radial pulses felt • Blood pressure recorded in lower limbs and left arm, but not recordable in right arm. BP similar in 3 limbs, high-normal(systolic 70-80mmHg, diastolic 40-50mmHg)

5. Abdomen • no exomphalos • large/thick umbilical cord, normal 3 vessels present • firm, large mass felt in left flank. Most likely renal mass. No bruit heard. No overlying bruising suggestive of trauma to abdomen • Normal male genitalia • Central Nervous System – active baby. Moving limbs, but right arm less - ?painful

6. Assessment: • Large-for gestational-age male infantof diabetic • Hypoglycaemia • Mild respiratory distress - transient tachypnoea of newborn/ hyaline membrane disease • Left flank mass – most likely renal origin. Possibly nephroblastoma/neuroblastoma • Evidence of spontaneous acute vascular (arterial) occlusion in right arm

7. Management • Intravenous fluids commenced (potassium-free Neonatalyte) • Nasal prong oxygen applied. Transcutaneous oxygen saturation 95% • Called for help! (acutely threatened limb) • Surgical opinion sought • Came to see infant within an hour • Suggested local massage over area of suspected arterial occlusion to try to disperse clot • Advised initiating anticoagulation with Heparin – loading dose followed by maintenance, intravenously

8. Reluctant to start thrombolytic therapy as risks (intracranial haemorrhage) outweigh possible benefits • Predicted probable tissue loss • Counselled mother regarding baby’s condition • Angiogram not indicated at that stage

9. Investigations and Specialist Consults • Full Blood Count • Haemoglobin – 13.7g/dl • Haematocrit - 0.47 • Platelets – 127 • Urea and electrolytes • Normal • INR and PTT (following day, on Heparin) • normal

10. Cardiology consult • Cardiology opinion sought (day 2 of life) to exclude intracardiac lesion predisposing to embolic events (hypertrophic cardiomyopathy, intracardiac thrombus) • Echocardiogram normal • Advised angiogram if arm not improving, or if new evidence of vascular occlusions • Advised thrombophilic workup

11. Haematology consult • Haematologist advised thrombotic screen, not immediately. Generally after 6 weeks as some factors may be abnormal because of therapy, or the acute thrombosis • Advised Antiphospholipid screen on mother – maternal antibodies may predispose to thrombosis in infant • Screen negative • Suggested anticoagulation with Low Molecular Weight Heparin (Clexane – Enoxaparin) rather than Unfractionated Heparin • Easier administration – subcutaneous vs intravenous • More predictable dose-response • Easier to monitor with Anti Factor Xa levels. Aim for 0.5-1.0 (therapeutic range) • Dose 1mg/kg subcutaneously 12 hourly

12. Radiology • Abdominal ultrasound performed day after delivery • Showed an enlarged adrenal gland (2cm) on the left, with inhomogeneous hypoechoic area within • ?haemorrhage • ?neuroblastoma • ?adrenal cyst • Both kidneys reported as normal • (Difficult to correlate with clinical impression of a large, hard renal mass. ?Actually feeling kidney pushed down by adrenal)

13. Cranial sonar requested to exclude any evidence of intracerebral thromboses, although clinically no concerns • Normal • Arterial doppler of right arm demonstrated flow within the subclavian artery, axillary artery, brachial artery and radial artery => confirmed arterial flow down to the hand. • Reported as unable to demonstrate any strictures along arterial path but arterial flow confirmed • (clinically no pulses however)

14. What next? • Discussed findings with radiologists, colleagues • ?any danger in anticoagulating if adrenal haemorrhage present • Decided unlikely to spread/worsen therefore not major concern • Would watch for signs of haemorrhage – haemoglobin dropping • Discussed with oncologist concerning possibility of this being a non-benign mass • Could afford to wait and watch • Even if congenital neuroblastoma, these tend to regress spontaneously • Therefore decision was to wait, whilst treating with Clexane, and follow up radiologically in about 1 week

15. Course and progress • Baby remained in NICU – as high care patient • Weaned off oxygen over next 3 days • Treated with Penicillin and Amikacin for 3 days, but no signs of sepsis • Blood glucose levels not problematic. No need for intravenous fluids by day 3, fed very well • NB. No umbilical arterial or venous catheters ever inserted • Blood pressure remained stable • Urine dipstix showed microscopic haematuria, which resolved • Normal urine output, repeat urea and electrolyte results were normal • No evidence of bleeding

16. Anti Xa levels monitored (level taken 3 hours after Clexane dose). In therapeutic range • Right arm developed superficial areas of discoloration, due to ischaemia (Day 2). However digits did NOT become gangrenous, nor did any skin ulceration ensue • Still unable to feel pulses distal to right axillary artery, but arm became pinker, warmer, and seemingly less painful • No new evidence of thromboses detected during stay

17. CT abdomen performed the following week (superior to ultrasound, MRI probably not necessary) • Left adrenal mass most likely an adrenal haemorrhage • Radiologist suspected renal vein thrombosis - left kidney also looked abnormal • Doppler ultrasound performed – confirmed left renal vein thrombosis • Renal vein thrombosis could explain ipsilateral adrenal haemorrhage • Now evidence of both arterial and venous thromboses • Renal vein thrombosis not too unusual in Infant of Diabetic, but NOT polycythaemic, and why the arterial occlusion?

18. Contacted haematologist again with new findings • Recommended thrombotic screen at this stage • Clexane not expected to alter most of results • If thrombophilic tendency detected, would • Explain findings in this patient • Determine duration of treatment • Results: • Fibrinogen – 3.10g/l (N) • Antithrombin III function – 59% (N) • Protein C function – 31% (N) • Protein S - 52% (N) • APC resistance ratio normal – no APC resistance demonstrated • Factor V Leiden mutation not detected • Prothrombin G20210A mutation not detected

19. To add to the confusion… • Day 9 – felt a firm mass just proximal to right antecubital fossa (affected arm) • 3cm X 2.5cm • Not pulsatile, not fluctuant, no overlying skin discoloration • ?related to thrombus in arm, but distal to original occlusion • ??related to massaging the arm on Day 1 – possibly fat necrosis • Ultrasound suggested a lipoma, (clinically did not feel like one), less likely a haematoma

20. Further discussions with colleagues and cardiologist led to decision to perform a CT angiogram • In light of thrombi in arterial and venous systems • To ensure no underlying vascular abnormalities (?aneurysms/stenoses) predisposing to further thrombotic events • Performed under general anaesthetic by a team experienced in neonatal CT angiography • Findings (17 Dec 2009) • Dystrophic calcifications in relation to left renal vein, adrenal gland and kidney • Left adrenal gland and kidney enlarged • No flow demonstrated in left renal vein • No arterial flow bilaterally from level of trifurcation (legs)

21. Deep venous system both lower legs poorly visualised (?thrombosed). Collateral flow demonstrated • Upper limb arteries and veins patent • Further evaluation with Doppler ultrasound recommended • Doppler ultrasound repeated following day • Flow present in left renal vein • No evidence of thrombosis • Good flow noted in arteries of lower limbs

22. Final outcome • Baby discharged 18 December 2009, Day 16 of life • Lump on right arm diminishing in size • Discharge weight 5.36kg • Plan: to come in twice daily for Clexane injections until mother confident to continue with administration herself

23. Follow up • Seen one week later – all going well. Mother started giving Clexane herself • Seen in January for follow up. Pulses now felt in right arm, renal mass much smaller, no complications of heparin therapy, anti Xa level 0.44 • Plan is to remain on Clexane for 3-6 months • Should follow up closely for renal damage secondary to renal vein thrombosis • NB – omit Clexane day before vaccines due

24. Thromboembolic disorders in neonates • Concentrations of various components of coagulation system differ greatly between neonates and adults • Age-appropriate reference ranges must always be used when interpreting results • Despite striking differences in levels of individual components, neonatal coagulation somewhat more rapid or robust than an adult’s

25. Neonate’s haemostatic system delicately balanced • Neither bleeding nor thrombosis common in healthy, term neonates • However -number of perinatal conditions can disrupt the balance, increase risk for haemorrhage or thrombus formation

26. Developing haemostatic system has decreased concentrations of • procoagulant proteins • naturally occurring anticoagulants • haemostatic control proteins • Overall – tendency to a prothrombotic state • Co-existence of inherited risk factors with acquired risk factors (sepsis, perinatal asphyxia, polycythaemia) =>thrombo-embolic states • Virchow’s triad – vessel wall damage, stasis/turbulent flow of blood, hypercoagulability of blood

27. Incidence – varies depending on type of thromboses reported, and methods of screening • Relatively rare, obviously more common in an ICU setting (5.1 per 100 000 live births, 2.4 per 1000 NICU admissions) • Term and preterm infants • Male = female, except renal vein thrombosis males > females • Approximately 90% of neonatal venous thromboses associated with central venous catheters (iatrogenic)

28. Neonatal thromboembolism Arterial thromboses Venous thromboses Catheter-related thrombosis (non-cardiac) Intracardiac thrombosis, thrombosis associated with congenital heart disease Renal vein thrombosis Portal vein thrombosis Cerebral sinovenous thrombosis • Ischaemic Perinatal Stroke • Iatrogenic arterial thromboses • Spontaneous arterial thromboses

29. Risk Factors Maternal Neonatal Central catheters Congenital heart disease Sepsis, necrotisingenterocolitis Perinatal asphyxia Respiratory distress Dehydration, shock Polycythaemia Surgery Medications Prothrombotic disorders • Diabetes • Thrombotic states in pregnancy • Preeclampsia • Chorioamnionitis • Prolonged rupture of membranes • Autoimmune disorders • Oligohydramnios

30. Ischaemic Perinatal Stroke • Constitutes majority of arterial thromboses • Occurs within 2 days after birth, up to 28 days postnatally • Signs – seizures, lethargy, hypotonia, poor feeding, apnoea • 20-63 per 100 000 live births • Most in left hemisphere, distribution of middle cerebral artery • Numerous potential risk factors • Prothrombotic disorders (hereditary) with/without other risk factors contributing factors

31. Iatrogenic arterial thromboses • Mainly related to complications from umbilical arterial catheters (UAC’s), peripheral arterial catheters, and femoral arterial catheters • Been shown to occur in up to 1 in 5 babies who have had an UAC placed • Complications – mesenteric ischaemia, hypertension, renal dysfunction/failure, limb loss • High positioning fewer complications • Suggestive signs – line dysfunction, extremity blanching/cyanosis, persistent thrombocytopenia, sepsis

32. Spontaneous arterial thromboses • Extremely rare • Usually involve aorta • Mimic congenital heart disease • Signs – decreased pulses, cool, mottled extremity • Treatment of arterial thrombosis • depends on clinical symptoms, location • Observation, supportive care • Anticoagulation • Fibrinolytic therapy • Surgery • Goal – to restore blood flow if there is limb/organ ischaemia

33. Catheter-related thrombosis (venous) • Central venous catheters improve neonatal care, but increase risk for thrombosis • Umbilical venous catheters (first week of life) • Peripheral venous catheters – parenteral nutrition, prolonged antibiotics • Study shown 1 in 5 patients with UVC’s had thrombus formation • Up to 65% in autopsy studies, with microscopic evidence of thrombi

34. Signs – persistent infection, thrombocytopenia, line dysfunction • CDC recommends use no longer than 14 days • Suspicion of venous thrombosis warrants prompt removal (some advise starting anticoagulant therapy first)

35. Intracardiac thrombosis • Central venous catheter placement into right atrium poses risk of damage to endocardium => thrombus formation • + line infections = intracardiac vegetations, dissemination of septic emboli • Can embolise to lungs or obstruct pulmonary artery • Thrombosis of superior vena cava also a complication of surgery for complex congenital cardiac disease

36. Renal Vein Thrombosis • Incidence been reported as 0.5 per 1000 NICU admissions • 70% unilateral(64% involving left kidney) • Malesmore frequently affected • Signs – macroscopic haematuria, palpable abdominal mass, thrombocytopenia, hypertension • Risk factors – perinatal asphyxia, dehydration, maternal diabetes • Acute complications – serious – adrenal haemorrhage, extension of clot into inferior vena cava, renal failure, hypertension, death • Chronic complications – most suffer complete, cortical, or segmental infarction of affected kidney/s and/or hypertension

37. Genetic prothrombotic risk factors been detected in 43 – 67% of patients with renal vein thrombosis • Recurrence rare, related to underlying thrombophilia • Therefore comprehensive prothrombotic evaluation recommended in these patients • Diagnosed on ultrasound with Doppler • Enlarged, echogenic kidneys, attenuation/loss of coticomedullary differentiation, absence of flow in main or arcuate renal veins • Treatment controversial • No large, randomised trials • Loss of renal tissue in most cases reported, irrespective of treatment approach

38. Treatment (contd) • Unilateral – absence of uraemia/extension into IVC => supportive care with monitoring for extension =>OR anticoagulation with unfractionated or low molecular weight heparin for up to 3 months With extension into IVC =>anticoagulation recommended for 3 months Bilateral renal vein thrombosis with renal failure =>thrombolytic therapy plus anticoagulation with unfractionated heparin followed by anticoagulation with unfractionated or low molecular weight heparin Fibrinolytic therapy been found to restore renal function in patients with bilateral RVT, but no effect in those with unilateral RVT

39. Portal Vein Thrombosis • Risk factors include sepsis/ oomphalitis or UVC use • Spontaneous resolution relatively common • However once detected, need to follow up closely for development of portal hypertension (up to 10 years later) • Cerebral Sinus Thrombosis • Symptoms include fever, seizures, lethargy • Large majority have predisposing risk factors and prothrombotic traits (Protein C or S deficiency), lupus anticoagulant, SLE in mother

40. Genetic risk factors • Mutations results in prothrombotic phenotype by causing • Deficiency/dysfunction of an inhibitor of haemostasis (Protein C, S, Antithrombin III) • Overproduction of a procoagulantprotein (Prothrombin) • Deficiency/dysfunction of fibrinolysis • Endothelial damage (antiphospholipid antibodies) • Homozygous or compound heterozygous disorders usually present in newborn period with SEVERE clinical manifestations • Surprisingly, even in individuals with a mutation and multiple acquired risk factors, many do not develop thromboses • High prevalence of multiple thrombophilic gene mutations in white population

41. Infants with multiple mutations and symptomatic thrombosis are at risk of recurrence, however usually in setting of other comorbidities • No recommendations on secondary prevention of thromboses in infants with thrombophilia • Nevertheless, many experts recommend screening in a neonate with symptomatic thromboembolism, regardless of other acquired risk factors • Majority of spontaneous events (not catheter-related) either due to • Multiple haemostatic prothrombotic defects or • Combination of prothrombotic defects and environmental or clinical conditions

42. Circulating maternal antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibody) can cause postnatal thrombosis • Therefore should also be excluded, easily performed with maternal blood • Transient effects • Recommended that prothrombotic evaluation be done at least 6 weeks after the event • Proteins may be lowered by the event • Anticoagulant should be stopped 2 weeks – 1 month before performing protein-based assays • DNA-based assays not affected by treatment nor thrombosis • Amount of blood required limitation in neonates, therefore use laboratory in an experienced tertiary care centre

43. Thrombolytics • Recombinant Tissue Plasminogen Activator only considered for limb- or organ-threatening postnatal thrombosis, acute atrial clots • Limited number of studies • Does not inhibit clot propagation therefore infused WITH heparin

44. Role of surgery • Microsurgical techniques combined with thrombolytic regimens can rapidly restore blood flow, avoid tissue loss, no major bleeding complications • Indications – significant arterial thrombosis, particularly from peripheral arterial line • Only in an experienced institution

45. Possible causes in this patient • Infant of diabetic - risk of thromboembolism • Renal vein thrombosis well-described • Number of cases described with arterial thrombosis of upper limb with or without concomitant RVT • Pathogenesis of thrombotic tendency in infant of diabetic not fully understood • Polycythaemia main reason (however this patient not polycythaemic) • ?deficiency of natural anticoagulants such as Antithrombin III • ?abnormalities of renal capillary vasculature • ?placental damage leading to leakage of placental thromboplastin or other coagulation initiators into fetal blood • ?free fatty acids and phospholipids may cross placenta and affect platelet function in poorly controlled diabetics

46. No other risk factors in this infant • Prothrombotic screen normal/negative • No asphyxia, no sepsis, no umbilical catheters inserted • Suggested that sheer size of infant may have predisposed to stasis of blood flow in the affected arm, due to pressure

47. Apparently well-known fact that infants with renal vein thrombosis can have simultaneous evidence of upper limb/intracerebral arterial embolism • Thrombus dislodges => travels up IVC => right atrium => foramen ovale => circulation supplying head and upper limbs

48. Learning points • Renal vein thrombosis (RVT) presents with a renal mass • Missed on initial ultrasound. ‘Luckily’ patient had another thromboembolic event which required treatment or may have missed treating RVT • RVT can embolise to arterial circulation through the foramen ovale in a neonate