Neonatal arterial thrombosis: an arcane COVID sequelae

Abstract

We describe a case of a term neonate with a swollen right arm and weakened pulses, diagnosed with arterial thromboembolism in the right axillary and brachial arteries. Treatment involved heparin, followed by enoxaparin, resulting in significant improvement. Maternal SARS-CoV-2 infection during pregnancy was considered as a potential factor, supported by the newborn’s reactive COVID antibodies. The authors hypothesise a potential correlation between neonatal thrombosis and maternal SARS-CoV-2 infection during pregnancy. It is important to note that this association remains speculative and warrants further investigation for validation. The case underscores the importance of recognising and managing neonatal arterial thrombosis, especially in the context of maternal illness. We discuss the case in detail and review current knowledge on this condition.

Background

Thromboembolism is a rare phenomenon in the neonatal period, although when it does occur there will be an increase in severity of complications.¹ The incidence of symptomatic neonatal thromboembolism is 0.5 per 10 000 live births. Even though we have a thorough grasp of the adult haemostatic system, serious complications can occur if thromboembolism is not detected at birth. While the effects of SARS-CoV-2 infection during pregnancy are unknown, many research lend credibility to the idea that mother-to-child transmission of SARS-CoV-2 can occur through the placenta in utero.² COVID-19 may lead to a thrombotic condition due to inflammation, endothelial dysfunction, platelet activation and blood stasis. This hypercoagulable state is essential during pregnancy due to its innate prothrombotic state and could provide an additional risk.³ Histopathological examinations of placental tissue have revealed decreased fetal vascular perfusion, vascular thrombi and arteriopathy in COVID-19 mothers.^{4 5}

Case presentation

A term female baby was born to a G2P1L1 mother with gestational diabetes and pregnancy-induced hypertension at 38 weeks and 5 days of gestation via elective lower uterine segment caesarean section with forceps application. Birth weight was 3380 g (50th-90th percentiles). Apgar scores were 9 at 1 and 5 min. At birth, it was noticed that there was oedema of the right arm which extended from the elbow down below distally until the wrist, with three constriction-like bands 2 cm below the elbow, at the wrist and mid-way between the two (figure 1A). Similar but minimal findings were seen in the left arm as well (figure 2A). Capillary refill was approximately 4 s. Bilateral brachial and radial pulses were feeble, and a provisional diagnosis of amniotic band sequence was made. The baby was admitted into the neonatal intensive care unit for observation. Preliminary investigations, coagulation studies and inflammatory markers were ordered, which revealed thrombocytopenia and elevated D-dimer levels. Ultrasound and Doppler scans of the bilateral upper limbs were performed, and an occlusive echogenic thrombus was noticed within the distal right axillary and proximal brachial arteries which confirmed the diagnosis of right axillary arterial thrombosis. While the clinical presentation suggested the possibility of amniotic band sequence initially, further diagnostic investigations, including ultrasound and Doppler scans, were performed to confirm the diagnosis of arterial thrombosis. Basic thrombophilia screen which included protein C, protein S and antithrombin III levels was within normal limits. The maternal history did not reveal any previous instances of suspected or confirmed COVID-19 infection, adding complexity to the consideration of the potential link between neonatal thrombosis and SARS-CoV-2 exposure during pregnancy. However, in view of significant maternal illness of fever and cough during the last few days of second trimester and the COVID antibodies immunoglobulin G (IgG) test done in the newborn at 24 hours of life was found to be reactive and a diagnosis of neonatal arterial thrombosis occurring secondary to maternal SARS-CoV-2 infection was considered. The mother was screened for SARS-CoV-2 at the time of delivery and was found to be negative. Maternal basic thrombophilia workup suggested no abnormality, factor 7 was within normal limits. Placental histopathology revealed no abnormality. In view of thrombocytopenia, platelets were transfused prior to heparin infusion. Heparin was administered intravenously following which clinical along with radiological improvement was seen with a reduction in swelling, with an improved capillary refill of less than 3 s and stronger peripheral pulses. Similarly, reduction of swelling was noted in the left upper limb as well. Platelets and coagulation profile were monitored during the infusion serially and heparin infusion was tapered and stopped by day 3 and then followed by subcutaneous enoxaparin for a total of 6 weeks.

Figure 1.

(A) Clinical presentation of right upper limb at admission (B) at week 6 of follow-up, decrease in limb girth and ischaemic features noted.

Figure 2.

(A) Clinical presentation of left upper limb at admission (B) at week 6 of follow-up, improvement in movement noted with diffuse non-tender subcutaneous nodules.

Investigations

A sepsis screen sent at 6 hours of life as per our unit protocol revealed thrombocytopenia (83 000/L) with raised C reactive protein levels (8.3 mg/dL). Ultrasound and Doppler scans of the bilateral upper limbs done were suggestive of an occlusive echogenic thrombus with more than 50% stenosis and increased velocity in the distal right axillary and proximal brachial arteries extending for approximately 2 cm (figure 3A). Below the thrombus, monophasic flow was demonstrated through the brachial, radial and ulnar arteries. Baseline investigations at the initiation of heparin therapy included coagulation profile, inflammatory markers, liver and renal function tests, which revealed thrombocytopenia, 100,000/L with a significantly elevated D-dimer value (ie, 30.5 mg/L) and interleukin-6 value of 17.7 pg/mL. Thrombophilia screening which included protein S, protein C and antithrombin III activity was normal. Mothers’ thrombophilia workup showed no features suggestive of maternal thrombophilia attributing to neonatal thrombosis. COVID IgG antibodies test done in the newborn at 24 hours of life in view of significant maternal illness of fever and cough during the last few days of second trimester was found to be reactive (5.9). By diagnosis of exclusion, neonatal arterial thrombosis was taken into consideration as a COVID sequelae. This was followed by serial monitoring of coagulation profile and platelets during administration of heparin therapy. The thrombus on imaging showed serial reduction with the final scan at the end of 6 weeks of treatment showing 1 cm of thrombus (figure 3B). Echocardiography and neurosonogram done to rule out multisystem involvement showed no evidence of arterial thrombus. Subsequent Dopplers showed significant reduction with improved haemodynamic circulation.

Figure 3.

(A) Doppler of right upper limb showing arterial thrombus approximately 2 cm in size. (B) Doppler showing thrombus reduced to approximately 1 cm in size at 6-week follow-up.

Differential diagnosis

Clinical presentation at birth first led to the diagnosis of amniotic band sequence. In view of signs of acute ischaemia, diagnosis of thrombosis was considered which was confirmed by serial Doppler ultrasonography scans. While gestational diabetes was considered a possible factor contributing to neonatal thrombosis, it is important to clarify that gestational diabetes primarily affects blood glucose levels and insulin regulation during pregnancy. However, it is not typically directly linked to an increased risk of neonatal thrombosis. Neonatal thrombosis is more commonly associated with factors such as maternal infections, placental abnormalities, genetic thrombophilia disorders or specific medical conditions in the neonate, and all of these conditions were ruled out as mentioned in the case report.

Treatment

Heparin infusion was administered intravenously for 72 hours initially, first at a loading dose of 75 U/kg, followed by a maintenance dose of 28 U/kg/hour. In view of thrombocytopenia, platelet transfusion was done prior to initiation of heparin therapy. Platelets and coagulation profile were serially monitored. Over 72 hours of heparin infusion, it was tapered gradually and stopped and a therapeutic dose of subcutaneous enoxaparin (1.5 mg/kg) two times per day was administered. As there was radiological and clinical improvement the dose was changed to prophylactic dose of 0.75 mg/kg 12th hourly which was given for a total duration of 6 weeks.

Outcome and follow-up

The baby was continued on injection enoxaparin and followed up. On review, it was noticed that there was a significant clinical improvement. Oedema, erythema and paraesthesia of bilateral upper limbs decreased, and improvement in the movement of limbs was noted at the shoulder (abduction) and elbow (flexion and extension). Platelets and coagulation profiles were serially monitored and were found to be normal. A favourable outcome was noted by the end of 6 weeks of follow-up as there was a drastic increase in movement of the right upper limb with improved abduction at the shoulder, flexion at the wrists and grasp reflex (figures 1B and 2B).

Discussion

Spontaneous arterial thromboembolic episodes at birth necessitate prompt, therapeutic intervention. Due to placental fetal-umbilical pathology, these may begin in utero; however, the definite mechanism is unknown. The patent ductus could possibly allow a venous thrombus from the placenta or umbilical arteries to enter the systemic circulation and cause an embolism, although additional evidence is needed. Despite the cause of thrombosis, its formation in extremities could lead to detrimental effects such as tissue ischaemia and gangrene.⁶ Compared with older children and adults, neonates have varying levels of coagulation and fibrinolytic components. Antithrombin, protein C, protein S and fibrinolytic factors are also decreased. Newborns are more susceptible to thrombotic and bleeding issues than older kids are because of these variations in the haemostatic system. These are a possible mechanism for tissue ischaemia and newborn gangrene, and they mostly affect the umbilical arteries, aorta and limbs. The outcome will depend on how long the ischaemia lasts.¹ A systematic review done by Rashish et al⁶ in Canada, which included 53 newborns, revealed the most common site for thromboembolic events to be the umbilicus, causing embolism and vascular impairment, which were most commonly diagnosed using ultrasound. Anticoagulant usage, surgery and hyperbaric oxygen therapy were all examples of non-standardised treatment procedures and medication dosages. 32.8% mortality was noted. Identification of potential sequences of events contributing to the illness was made easier by recurrent aetiological traits such as congenital and acquired risk factors; however, the research was insufficient to support it.

Another case of a 38-week neonate with extensive arterial thromboembolism of the right upper limb noted at birth was reported from Australia with an MRI brain showing multiple intracranial pathology. The exact aetiology of thromboembolism was unknown, however, most likely to have originated in the placenta and traversed into the fetal circulation. Neurological implications could have occurred due to a clot which could have travelled via the carotids to the circle of Willis resulting in ischaemia. Management included intravenous heparin and subcutaneous enoxaparin on discharge. On follow-up, the child was noted to have right-sided hemiplegia with increased tone and brisk reflexes, microcephaly and speech delay.⁷ Recently, there has been a rise in inflammation in neonates involving various systems occurring secondary to maternal SARS-CoV-2 infection.⁸ A study done in Kolhapur, India, found an increase in the number of neonates with conduction abnormalities such as atrioventricular block or thrombosis with structurally normal hearts born to mothers with a history of COVID-19.

Maternal SARS-CoV-2 can cause a hyperinflammatory syndrome in neonates due to transplacental transfer of antibodies and immunomodulation. Neonates were diagnosed with neonatal multisystem inflammatory syndrome according to diagnostic criteria and received intravenous steroids and Ig. The management principles are based on a multidisciplinary approach-specialised supportive care and symptomatic management, along with treating suspected infections and considering specific interventions such as anticoagulation and surgery.⁸

Studies on the placental pathology of SARS-CoV-2 during pregnancy have shown a link between COVID-19’s propensity for coagulopathy and the potential for transplacental consequences for the fetus. In an examination of 20 placentas, 10 had fetal vascular malperfusion due to fibrin deposition or fetal vascular thrombosis.^{4 5} Another study done in New York included a preterm neonate with upper extremity necrotic lesions suspected to have complications related to in utero neonatal perfusion that happened due to a maternal COVID-19 infection. Even though the clinical course of the mother’s COVID-19 infection was asymptomatic with no other significant risk factors, this case raises significant doubts about newborn morbidity. Management included partial forearm salvage and hand amputation, along with symptomatic measures.³ Another case of fetal death in a COVID-19-tested positive mother was reported in Brazil. The virus was found in the placenta and in various fetal tissues. The fetal death was likely caused by significant vascular malperfusion, which was consistent with placental abnormalities (MRI and anatomopathological examination). Inflammation was also visible in the lung histology, which might have been a contributing factor. Monitoring coagulation and the inflammatory response in high-risk pregnant women using COVID-19 may help avoid unfavourable outcomes.² In a study done by More et al,⁹ a group of newborn babies who presented with multisystem involvement and SARS-CoV-2 antibodies was identified. With this background and investigations showing elevated inflammatory levels, there was a high index of suspicion attributing to COVID-19 sequelae. Increased response to immunomodulators along with symptomatic management was noted. Therefore, early recognition and anticoagulation therapy may help reduce the extent of function and tissue loss.

Patient’s perspective.

I was afraid when I learned of my daughters’ condition and feared that she would lose her arm. When both the limbs were affected, I had lost hope and had given up. After initiating daily injections, I could see the improvement in both hands and I am happy she has regained movement now. She is able to lift both her arms. My daughter has received injections for 6 weeks and she is now able to move her limbs and hold onto things efficiently.

Learning points.

• Prompt recognition of neonatal arterial thrombosis is paramount, particularly in the context of suspected maternal SARS-CoV-2 infection during pregnancy, to facilitate early intervention and optimise patient outcomes.

• Early recognition of neonatal thrombosis is critical for appropriate intervention, although the proposed link to maternal SARS-CoV-2 infection remains speculative.

• Appropriate treatment helps reduce the extent of function and tissue loss.

• Anticoagulation therapy must be administered along with serial monitoring of coagulation profiles to avoid risks and complications.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s)