Antiphospholipid syndrome (APS) is a multisystem autoimmune disease that is characterized by venous and arterial thrombosis, which may or may not be associated with pregnancy complications in the presence of antiphospholipid antibodies (aPL) [
The current study aims to review the existing case reports in the literature with regard to neonatal thrombosis and aPL through a retrospective study that focuses on the pathogenesis and the main clinical and laboratory manifestations and outcomes in these patients.
Patients were considered as having neonatal thrombosis associated with the presence of aPL if the onset of thrombotic episode occurred before 28 days after birth due to the presence of aPL [
The case reports in the literature were selected from PubMed and case series were excluded because they do not present well-structured papers that could respond to our study questions. The keywords used were neonatal, antiphospholipid syndrome, thrombosis, and antiphospholipid antibodies. References that were available in English, Spanish, and French and published during the period from 1987 to 2013 were reviewed. The articles were reviewed for demographic characteristics (race and sex), clinical manifestations (symptom onset and evolution), obstetric conditions (delivery type and maternal history), treatment, and immunological markers. Laboratories tests used for determining aPL and anti-beta-2-glycoprotein I (anti
Twenty-one cases of neonatal thrombosis and aPL were identified in 20 articles that were published as case reports during the period from 1987 to 2013.
The study reviewed 21 children, of whom 12 (57%) were males, 5 were females, and 4 were not specified. The average time of symptom onset occurred mainly within the first 48 hours (12/22). Cesarean section deliveries were reported in 11/20 cases due to preeclampsia (2), no progression of the delivery or fetal distress, and vaginal deliveries were reported in 7 cases. The gestational ages ranged from 27 to 41 weeks. Ten children were born preterm (before 37 weeks). Two children presented with sepsis and 2 with pneumonia. Two children required a central catheter.
Six mothers had only aPL without evidence of autoimmune disease, 7 had primary APS, 2 had secondary APS, and 6 were healthy. With regard to the aPL profiles in the neonates, 13 children had anti-cardiolipin antibodies, 6 had lupus anticoagulants, 4 had anti-
Clinical, laboratory, and therapeutic analyses of 21 patients with neonatal thrombosis and antiphospholipid antibodies.
Case | Reference | Sex | Delivery and newborn age | Clinical manifestation | Maternal history | Neonatal antibodies | Treatment | Evolution |
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1 | Finazzi et al. 1987 [ |
F | Preeclampsia cesarean delivery/20 days | Cyanosis in the left foot. US Doppler: left femoral artery thrombosis | Primary APS | Lupus anticoagulant | NR | Death on day 30 due to extensive aortic thrombus (autopsy) |
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2 | Sheridan-Pereira et al. 1988 [ |
F | Cesarean delivery/at birth | DIC and MV. |
Maternal APS | Lupus anticoagulant | Plasmapheresis and heparin | The peripheral pulses were normal on day 13 |
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3 | Silver et al. 1992 [ |
NR | Delivery NR/at birth | Right spastic hemiparesis. MRI: middle cerebral artery infarction | Mother with multiple sclerosis and primary APS | NR | NR | Improvement of the hemiparesis at 6 months |
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4 | Contractor et al. 1992 [ |
NR | Cesarean delivery/1 day | Left abdominal mass and hematuria. Renal vein and inferior vena cava thrombosis | Mother with aPL | IgG anti-cardiolipin | NR | Clinical improvement at day 7. The antiphospholipid profile disappeared at 4 months postpartum |
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5 | Tabbutt et al. 1994 [ |
M | Cesarean delivery/3 days | Aortic, left renal artery, middle cerebral and superior sagittal sinus thrombosis, sepsis | Primary APS | Prolonged APTT, aPL negative | Heparin and ATB | Favorable at 2 months |
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6 | Hage et al. 1994 [ |
M | Cesarean delivery/at birth | Hydrops fetalis with renal vein thrombosis | Healthy mother | Lupus anticoagulant | Mother was treated with tocolytic medications | Unfavorable. Fetal death |
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7 | Teyssier et al. 1995 [ |
M | Normal vaginal delivery/3 days | Convulsion due to cerebrovascular ischemia and massive bilateral adrenal hemorrhage | Mother with aPL | Anti-cardiolipin positive | Phenobarbital | Favorable. Normal EEG at 7 months after birth |
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8 |
de Klerk et al. 1997 [ |
M | Normal vaginal delivery/at birth | Seizures, blinking repeatedly, spasms on the right side of the head, hand, and foot (no longer than 3 minutes). Ischemic stroke at the level of the left middle cerebral artery | Mother with aPL | Lupus anticoagulant | Phenobarbital | Favorable after 1 year |
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9 | Navarro et al. 1997 [ |
NR | Cesarean delivery/3 days | Respiratory distress syndrome, pneumoperitoneum and abdominal livedo (mesenteric thrombosis) | Primary APS | IgG anti-cardiolipin | NR | Death on day 11 after laparotomy |
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10 | Akanli et al. 1998 [ |
NR | Cesarean delivery/6 hours | Apnea, cyanosis, and moderate hypotonia. Mechanical ventilation. Progressed with stroke in the left middle cerebral artery area | Mother with aPL | IgG anti-cardiolipin | NR | Seizures until 3 years of age |
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11 |
Chow and Mellor 2000 [ |
F | Cesarean delivery/48 hours | Focal seizure in the left hemibody. CT: cerebral ischemia | Primary APS | IgG anti-cardiolipin | Phenobarbital and phenytoin | Favorable. Normal neurological examination 5 months after birth |
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12 | Chow and Mellor 2000 [ |
M | Delivery NR/at birth | Right hemiplegia; later developed epilepsy. CT: ischemia at the level of the left middle cerebral artery | Primary APS | NR | NR | Unfavorable. Epilepsy |
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13 |
Tuohy and Harrison 2005 [ |
M | Preeclampsia, cesarean delivery/5 days | Anuria, paleness, and absence of pulse in the lower extremities. Aortic thrombosis | Primary APS | IgG anti-cardiolipin | rTPA | Death from renal failure on day 10 |
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14 | Soares Rolim et al. 2006 [ |
M | Delivery NR/20 hours | Thrombocytopenia, livedo reticularis; pericardial effusion; subclavian vein and external jugular thrombosis concomitantly with severe respiratory tract/central catheter infection | Secondary APS | IgG and IgM anti-cardiolipin | Immunoglobulin IV heparin and antibiotic treatment | Death |
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15 | Paro-Panjan et al. 2007 [ |
F | Normal vaginal delivery/13 hours | Seizures; ischemic stroke. MRI: occlusion of the left middle cerebral artery | Mother with aPL | IgG anti-cardiolipin. Mutation of the prothrombin gene polymorphism |
Phenobarbital | No neurological deficits after 1 year of follow-up |
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16 | Alshekaili et al. 2010 [ |
M | Normal vaginal delivery/5 days | Reduced spontaneous movement of the right limbs; ischemic stroke of the middle cerebral artery. Epilepsy. Late livedo reticularis (after 4 years) | Healthy mother | IgG anti-cardiolipin, IgG anti B2GPI. Factor V Leiden (G20210A allele) | Antiepileptic and anticoagulant | Favorable |
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17 | Cabral et al. 2011 [ |
M | Normal vaginal delivery/17 days | Irritability, abdominal distension, vomiting, bloody stools with signs of shock, necrotizing enteritis-exploratory laparotomy. ICC: after 13 months, started to exhibit tonic-clonic seizures and right hemiparesis. Stroke in the frontal, parietal, and right temporal lobes | Healthy mother | Lupus anticoagulant, IgG/IgM anti-cardiolipin, IgG and IgM anti-B2GPI. |
Low molecular weight heparin, acetyl salicylic acid, and phenobarbital | Favorable after 5 years of follow-up |
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18 | Bhat et al. 2011 [ |
M | Cesarean delivery/3 days | Sepsis. Bluish discoloration in the left lower limb (thrombosis of the left femoral artery); absence of popliteal pulse and prolonged capillary refill time | Mother with aPL | Lupus anticoagulant | Thrombolysis, urokinase/heparin, and antibiotic | Favorable |
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19 | De Carolis et al. 2012 [ |
M | Normal vaginal delivery/1 day | Severe respiratory distress due to pneumonia. Thrombosis in the superior sagittal sinus | Healthy mother | IgG anti-cardiolipin | NR | Normal neurological development after 1 year |
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20 | Merlin et al. 2012 [ |
M | Normal vaginal delivery/3 days | Right clonic seizures. |
Healthy mother | IgG anti-cardiolipin and IgG B2GPI | 100 mg of valproate and aspirin every other day | Normal development and neurological examination after 1 year |
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21 | Sousa et al. 2012 [ |
F | Cesarean delivery/8 hours | Focal and multifocal seizures and left hemiparesis. MRI: ischemic stroke | Healthy mother | IgG anti-cardiolipin, IgG B2GPI, and lupus anticoagulant positives (de novo synthesis). |
Anticonvulsants and aspirin | L side body strength improved and monoparesis in the left upper limb persisted after 1 year. Seizures improved at 3 months of age |
APS: antiphospholipid syndrome. DIC: disseminated intravascular coagulation. MV: mechanical ventilation. rt-PA: recombinant tissue plasminogen activator. aPL: antiphospholipid antibodies. MRI: magnetic resonance imaging. IV: intravenous. B2GPI: B2-glycoprotein I. PT 20210G>A: heterozygosity for the prothrombin gene. PAI-1 675G>A: homozygosity for the plasminogen activator inhibitor-1 gene. 1298C/C MTHFR: homozygous mutation of the methyltetrahydrofolate reductase gene. PAI-1 844A/A and 675 4G/4G: double heterozygosity for the inhibitor plasminogen activator. C677T: heterozygosity for the methylenetetrahydrofolate reductase gene polymorphism. NR: not reported.
Arterial involvement was present in 17 of the 21 cases. Stroke was the most prevalent clinical manifestation, occurring in 12 of the 17 cases, along with impairment of the middle cerebral artery (10/17). The aorta, mesenteric, and femoral arteries were involved in 2 cases and the renal artery in 1 case. Venous involvement was observed in 5 of the 21 children; in 3 of them, only the peripheral circulation was affected while, in the other 2, the central circulation was also involved. Convulsions were observed in 9 of the 21 patients; these were usually secondary to stroke, and thus the development of epilepsy was uncommon and reported in only 1 patient. One patient developed catastrophic APS, another presented with Sneddon’s syndrome, and a third presented with thrombocytopenia.
The treatments were mainly based on the use of symptomatics such as antiepileptic drugs (8/21). One patient was treated with immunoglobulin for thrombocytopenia, 2 patients were subjected to thrombolysis (thrombosis of the femoral artery and aorta), and 6 patients received heparin. Fourteen (66.6%) of the 21 children had favorable outcomes, 2 had partial improvements (1 persisted with monoparesis in the left arm and another developed epilepsy), and 4 (19%) died (renal vein thrombosis, mesenteric artery thrombosis, aortic thrombosis, and subclavian and jugular vein thrombosis). Of the 11 children who had strokes, 9 had favorable outcomes. The mean time of follow-up was 1 at 5 years (Table
It has been suggested that pathogenic aPL could be absorbed at the placental level. Since placental passage is limited, this may explain the relative low frequency of clinical events in neonates [
Autoimmune diseases are very rare in newborns due to their immature immune systems, which will become fully developed by the age of 3 [
Among the prenatal risk factors, gestational diabetes, preeclampsia, intrauterine growth restriction, maternal APS, and systemic lupus erythematosus (SLE) are predisposing factors to thrombosis in neonates [
Prematurity, asphyxia, respiratory infections, sepsis, central catheter, and parenteral nutrition seem to be the most common perinatal risk factors [
Another risk factor that appeared to be associated with the thrombotic events in neonates is congenital thrombotic gene mutation. Deficiencies in proteins C and S and mutations in the coagulation factors appear to be associated with thrombotic events in newborns, thus reflecting an imbalance between the coagulants and anticoagulant activity [
Gene mutations were observed in 4 cases [
Unlike adults, in whom deep venous thrombosis was found in 39% of the cases [
In a study that evaluated the risk of thrombosis in pediatric patients, 28 children with APS at an average age of 13 years were analyzed; venous thrombosis, stroke, and thrombocytopenia were the most commonly observed manifestations [
Perinatal stroke occurs in 1 of every 4000–5000 live births [
Newborns from mothers with aPL had an increased risk of stroke [
Although stroke and TIA correspond to 50% of the arterial thrombosis cases [
Convulsive seizures usually have 2 peaks of incidence. One occurs in the first year of life, during which pre-, peri-, and postnatal processes facilitate central nervous system aggression. The other peak occurs in the seventh decade of life, during which there is a higher incidence of degenerative neurological diseases [
During the neonatal period, seizures are mainly attributed to neonatal asphyxia, metabolic disorders, or infections [
This syndrome is characterized by 3 main manifestations: ischemic stroke, livedo reticularis, and antiphospholipid antibody positivity [
Thrombocytopenia is a manifestation present in nearly 30% of APS cases [
Recently, the CAPS Registry studied catastrophic events in children and observed that 10.3% (45/446) patients were before 18 years of age. Overall, 32 (71.1%) patients were female and the mean age was
We observed only 1 case report of catastrophic APS in which the newborn was triply positive for aPL associated with prothrombin and plasminogen activator inhibitor gene mutations that might have amplified the risk of thrombosis in this patient. Despite the triple positivity associated with prothrombotic gene mutations and the most serious manifestations of APS, the treatment was early and effective. Case of [
The lack of specific guidelines for neonates with thrombosis associated with aPL may be explained due to immaturity of the fibrinolytic system, suggesting that the patients should be followed up past puberty for validation of risk [
Treatment for neonatal thrombosis and antiphospholipid antibodies comprises anticoagulant therapies such as aspirin, heparin, and warfarin [
For neonatal thrombosis and antiphospholipid antibodies APS, in addition to the anticoagulants, treatments are based on the comorbidities present in the newborns; particularly, infections are treated with antibiotics and clinical manifestations such as seizures and respiratory distress are treated with antiepileptics (e.g., phenobarbital) and support therapy (e.g., mechanical ventilation), respectively. Other treatment modalities were offered; for example, 1 patient received immunoglobulin due to thrombocytopenia, [
There are no validated criteria for neonatal APS. The publications were heterogeneous with regard to the year of publication and advances in knowledge of the syndrome, such as the discovery of new antibodies and a better understanding of disease pathogenesis and the inclusion of new therapies.
Stroke was the most frequent clinical manifestation associated with antiphospholipid antibodies in neonates, and children who suffer strokes seem to develop favorably. Preterm birth was an additional perinatal risk factor for thrombotic manifestations.
From the findings in the current study, we conclude that neonatal thrombosis and antiphospholipid antibodies are a rare event, even in mothers who have antiphospholipid antibodies. The development of thrombotic manifestations in neonates seems not to be associated exclusively to the aPL, but their etiology may be linked to pre- and perinatal events or coagulation factor gene mutations.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Jozélio Freire de Carvalho received Grants from the Federico Foundation and CNPq (300665/2009-1).