Neonatal intracardiac thrombosis secondary to transplacental transfer of maternal antiphospholipid antibodies-a case report and review of the literature

Abstract

Background

Maternal antiphospholipid immunoglobulin (Ig) G antibodies can cross the placenta, placing neonates at uncertain risk for thrombosis. There are no previous reports of neonatal intracardiac thrombosis (ICT) in the context of anticardiolipin antibodies (aCL).

Key Clinical Question

What were the clinical manifestations, management, and outcomes for a mother and her child with ICT secondary to presumed transplacental transfer of aCL?

Clinical Approach

A 2-week-old female presented with reduced feeding and was found to be poorly perfused with significant lactic acidosis. A mobile mass was noted near the left atrial appendage on the echocardiogram and confirmed on cardiac magnetic resonance imaging. Magnetic resonance imaging of the brain was normal, with no evidence of stroke. The aCL IgG titers returned highly positive for the infant (115.3 IgG phospholipid (GPL)-Unit [U]/mL) and mother (>160 GPL-U/mL; >99th percentile local reference is ≥20 GPL-U/mL). There were no other overt risk factors for thrombosis. The infant received 6 months of enoxaparin until aCL normalized. There remains a small calcified thrombus adherent to the left atrial wall. At 2 years old, the child remains healthy with no cardiac, neurologic, nor thrombotic sequelae.

Conclusion

This is the first report of neonatal ICT presumed secondary to maternal aCL. The outcome was favorable with anticoagulation management. Further research is needed in the area of transplacental antiphospholipid antibody transfer, identification of neonates at risk, and optimal clinical management.

Essentials

• •Transplacental transfer of maternal antiphospholipid antibodies places neonates at uncertain risk for thrombosis.
• •Tertiary care pediatric center.
• •We describe the first reported case of neonatal ICT in the context of maternally-derived aCL.
• •Consider testing for aPL in unusual neonatal thrombosis, particularly if arterial location, lacking thrombotic risk factors, or in mothers with APS.

1. Introduction

Intracardiac thrombosis (ICT) is uncommon in the pediatric age group but may occur in those with reduced cardiac function or congenital heart lesions [1]. In neonates, ICT has most frequently been reported in premature infants, with additional risk factors including sepsis, central venous catheterization, dehydration, and polycythemia. In the absence of overt thrombotic risk factors, acquired thrombophilia may be considered.

Antiphospholipid syndrome (APS) is a systemic autoimmune disorder characterized by an increased risk of thrombosis and pregnancy complications in the setting of persistently positive antiphospholipid antibodies (aPL) [2]. These antibodies are thought to promote aPL-mediated clinical events through interactions with antigenic targets on multiple cell types (endothelial cells, monocytes, platelets, trophoblasts, neuronal cells, and fibroblasts) and upregulation of tissue factor expression, potentiation of platelet aggregation, inhibition of anticoagulant proteins, complement activation, and release of neutrophil extracellular traps, among other mechanisms [3,4]. As maternal IgG antibodies can cross the placenta, neonates may be at risk for thrombotic episodes, but this absolute risk remains uncertain. We aimed to describe the clinical manifestations, management, and outcomes for a mother and her child with ICT secondary to presumed transplacental transfer of aCL.

2. Case Report

A previously well 2-week-old neonate presented to our emergency department with a 2-day history of poor feeding. She was born to a 31-year-old G3T1P0A2 mother by an uncomplicated vaginal delivery at 39 weeks gestational age. The maternal history was significant for 2 prior early (<10 weeks gestational age) pregnancy losses, and she received acetylsalicylic acid (ASA) 81 mg daily and vaginal progesterone due to the history of losses.

On presentation, the neonate was found to be poorly perfused, requiring fluid resuscitation and inotropic support. The initial capillary blood gas showed significant lactic acidosis with a pH of 6.97 and a lactate of 10.5. The chest X-ray demonstrated a normal cardiac silhouette, and a 12-lead electrocardiogram showed a normal sinus rhythm. An infectious workup returned negative, including a blood culture and extended viral testing for respiratory pathogens. The initial echocardiogram revealed moderately reduced left ventricular function and a homogeneous mobile mass near the orifice of the left atrial appendage without inflow tract obstruction (Figure). With supportive care alone, the cardiac function improved within hours, and inotropic support was discontinued. Cardiac magnetic resonance imaging (MRI) was consistent with a thrombus. Ultrasound with Doppler assessment of the abdomen and lower extremities and a brain MRI were normal.

Figure.

Four-chamber view of the initial echocardiogram demonstrating a left atrial mass (red arrow). 2D, 2-dimensional.

Thrombophilia investigations were pursued given the unusual finding of ICT in the absence of other causes, such as congenital heart lesions, cardiomyopathy, or arrhythmia. Anticardiolipin antibody (aCL) IgG titer returned highly positive at 115.3 IgG phospholipid (GPL)-Units (U)/mL (>99th percentile local reference is ≥20 GPL-U/mL). Anti-β2 glycoprotein antibody (aβ2GP1) IgG and lupus anticoagulant (LAC) testing were negative. The aCL and aβ2GP1 IgM were not tested due to local protocols. Factor (F)V Leiden and FII 20210A gene testing were normal, along with protein C activity at 0.47 U/mL, protein S activity at 1.14 U/mL, and antithrombin activity at 0.8 U/mL, which were all within the normal range for age.

Maternal testing was arranged, given the strong suspicion of transplacental transfer of antibodies. Maternal results showed a highly positive aCL > 160 GPL-U/mL, confirmed on repeat testing more than 12 weeks apart. The aβ2GP1 and LAC were negative. The maternal antinuclear antibody titer was 1:80, while extractable nuclear antigen and anti–double-stranded DNA antibodies were negative, and she had no clinical features of systemic lupus erythematosus. Although maternal history was significant for 2 pregnancy losses <10 weeks of gestation, she did not meet the revised Sapporo criteria [5] or the American College of Rheumatology/European League Against Rheumatism APS criteria [2].

Anticoagulation was initiated with enoxaparin 1.5 mg/kg subcutaneously every 12 hours and titrated to achieve an anti-Xa level between 0.5 and 1 U/mL. Antimicrobials were discontinued within 48 hours. The infant continued enoxaparin until 6 months of age. The aCL titer fell to low positive (33.8 GPL-U/L) by 3 months and to negative (<1.6 GPL-U/L) by 6 months of age, consistent with transplacental acquisition. Cardiac MRI at 6 months demonstrated a small mass adherent to the left atrial wall, with imaging characteristics in keeping with a calcified thrombus, and echocardiogram findings were stable. Enoxaparin was discontinued, and the patient received low-dose ASA (5 mg/kg) for 4 weeks, which was then stopped based on family preference. At 2 years of age, the child remains well with no cardiac sequelae or recurrent thrombosis and normal neurodevelopment.

3. Discussion

We report a neonate with ICT in the setting of previously undiagnosed maternally derived aCL. In this case, no other prothrombotic risk factors were identified. Due to concerns about the mobility of the left-sided clot and the possibility of embolization, low-molecular-weight heparin was selected for initial treatment. Once aCL normalized, in keeping with transplacental transfer and not primary APS, anticoagulation was discontinued. Multidisciplinary consensus (including representation from hematology, cardiology, and rheumatology) led to the recommendation to treat with low-dose ASA for an additional 3 months based on the arterial location of the thrombus, broad use of ASA in APS [6,7], and tolerability and safety profile of the drug. This child remains healthy with a favorable outcome.

Upon literature review, there is 1 additional case of ICT in a neonate born to a mother with Sjogren syndrome but with negative aPL [8]. An intraventricular thrombus was noted on imaging and treated with tissue plasminogen activator. Given the maternal history of recurrent pregnancy loss and persistent noncriteria aPL, the authors proposed that the neonate’s thrombosis may have been secondary to maternal (seronegative) APS. In a prospective study of 138 mothers with APS, maternal transfer of aPL occurred in 34% of the pregnancies [9]. Transfer of aβ2GP1 was most common (43%) compared with aCL (25%) and LAC (20%). These pregnancies were most commonly managed with ASA and low-molecular-weight heparin alone (89/138, 64%) or in addition to steroids (25/138, 18%) or hydroxychloroquine (HCQ; 15/138, 11%).

Prospective studies have demonstrated that thrombosis is rare in infants born to mothers with APS. In a study of 141 infants born to mothers with APS, there were no thrombotic events over a 2-year follow-up period [9]. Similarly, in a cohort of 134 infants, there were no thrombotic events over 5 years of follow-up [10]. When thrombotic events have been noted among neonates with aPL, arterial location occurs more frequently. More than 80% of clots were arterial in 2 separate studies (arterial 17/21 [81%] vs venous 4/21 [19%] [11], and arterial 13/16 [81%] vs venous 3/16 [19%] [12]), with ischemic stroke being the most common manifestation. In both cohorts, aCL was the most prevalent aPL, positive in 50% to 62% [11,12].

Developmental hemostasis denotes the immature but relatively balanced coagulation system in young infants, characterized by lower levels of both pro- and anticoagulant proteins and altered fibrinolysis. With less developed compensatory mechanisms [13], the presence of high titer aPL may tip the scale toward a thrombotic event. Presumably, then, thrombotic risk should be reduced once the aPL have cleared from the circulation. Despite the relatively frequent occurrence of transplacental transfer of aPL, neonatal thrombosis is rare. Given that aPL alone does not result in spontaneous thrombotic complications, it is likely that aPL are one of several prothrombotic risk factors contributing to thrombus generation in neonates (“two-hit hypothesis”) [14]. Although the neonate in our case appeared clinically well prior to her acute presentation, it is possible that another occult risk factor was present, such as an unidentified infection.

Although thrombotic complications are uncommon events in infants born to mothers with APS, a large thrombus may be life-threatening or result in significant sequelae for the child. Some have recommended screening for aPL during the first week of life in neonates at risk [12]. The management of subsequent pregnancies, including neonatal surveillance, is not well defined. Another unanswered question is the role (if any) of primary prophylactic anticoagulation in neonates with aPL in the absence of thrombosis. Given the overall low incidence of thrombosis, the potential benefit of thromboprophylaxis in the neonate is outweighed by the bleeding risk, particularly in premature infants. Therefore, the authors recommend against its use. How to manage neonates with a previously affected sibling is unknown.

This case highlights implications not only for the neonate but also for the mother. Identification of persistent aPL warrants evaluation for an accompanying systemic diagnosis of APS and autoimmune disease. There is a lack of high-quality evidence to guide the management of future pregnancies. HCQ is an immunomodulatory drug that is used in severe autoimmune diseases and has been suggested as an adjunct in refractory obstetric APS treatment [15,16]. Retrospective studies have suggested that HCQ may reduce aPL titers [17]. It is unknown whether immunomodulation can lower maternal aPL titers and thereby reduce the amount of transplacental aPL transfer to a fetus, but this type of approach is biologically plausible and warrants further investigation.

4. Conclusion

In summary, neonatal thrombosis is a rare complication of maternally derived aPL. This is the first report of neonatal ICT secondary to maternal aCL. Clinicians should consider testing for aPL in unusual neonatal thrombosis, particularly in the setting of early presentation of arterial thrombosis in those lacking other clear thrombotic risk factors or in a mother with known APS.