Spontaneous intestinal perforation (SIP), a rare complication in neonates, was diagnosed in a preterm newborn. After surgery, small bowel histology showed acute ischemic changes and one area of perforation. Fibrin thrombus in the submucosal capillary vessels suggested a thrombotic mechanism in the pathogenesis. Subsequently, two severe asynchronous thrombotic events developed: cerebral sinovenous thrombosis and renal vein and inferior vena cava thrombosis. The neonate presented with hypercoagulability and factor V Leiden heterozygosity. This is the first association of SIP with inherited thrombophilia and thrombotic events in a neonate, suggesting hypercoagulability as a new research focus for pathogenesis of this enigmatic disease.
This case presents spontaneous intestinal perforation (SIP) followed by two severe thromboembolic events – cerebral sinovenous and renal vein and inferior vena cava thrombosis. The presence of three infrequent complications in a preterm neonate may not be a simple coincidence. A common risk factor in the pathogenesis of these diseases can be hypothesized.
A male neonate weighing 1340 g was born by cesarean section at 29 weeks of gestation, after 5 days of premature rupture of amniotic membranes and suspicion of chorioamnionitis. Amniotic fluid culture revealed the presence of Escherichia coli.
The mother was treated during pregnancy with low-molecular-weight heparin (LMWH) due to a history of repeated late spontaneous abortions, placental abruption, and presumed thrombophilia. However, no thrombophilic studies had been performed on the mother.
Apgar scores were 13 and 8 at 1 and 5 min, respectively. Mechanical ventilation was required and replaced with nasal continuous positive airway pressure after 10 h, and antibiotics were administered. Oral feeding was not initiated; blood, urine, and cerebrospinal fluid cultures showed negative results. An umbilical vein catheter was used for the first 6 days of life; thereafter, one central catheter was peripherally inserted into the brachial vein and peripheral lines were used.
On day 2, systemic deterioration was observed; pneumoperitoneum was diagnosed by X-ray. Laboratory analysis were as follows: hemoglobin 149 g/L (normal for age: 12–19 g/dL), WBC 2.2×109/L (5–21×109/L), platelets 95×109/L (150–450×109/L), prothrombin time (PT) 23.4 s (10.6–16.2 s), INR 1.72 (0.61–1.7), activated partial thromboplastin time (aPTT) 39 s (27.5–79.4 s), and fibrinogen 672 mg/dL (150–373 mg/dL).
Exploratory laparotomy revealed intestinal perforation 40 cm from the ileocecal valve. About 5 cm of necrotic small bowel were resected and an enterostomy was performed. Microscopic examination showed diffuse fresh hemorrhagic necrosis from the mucosa to the serosa, acute ischemic changes, multiple areas of muscularis propria thinning or disappearance, and one area of perforation. Normal ganglion cells were present. Fibrin thrombi were found in the submucosal capillary vessels (Figure 1).
Following surgery, the clinical condition of the patient improved, oral feeding was initiated, and weight gain occurred. On day 40, the patient’s condition deteriorated, showing poor feeding and neurological signs; a brain ultrasound (US) revealed bilateral ischemic changes. Doppler US and computerized tomography (CT) demonstrated deep cerebral sinovenous thrombosis in the straight sinus, with bilateral intraventricular and intraparenchymal hemorrhage. Laboratory values were as follows: hemoglobin 100 g/L (9.5–13 g/dL), WBC 5.2×109/L (5–19.5×109/L), platelets 130×109/L, PT 18 s (10–14.6 s), aPTT 39 s (26.9–62 s), and fibrinogen 500 mg/dL (150–414 mg/dL). The patient received supportive treatment. No thrombolytic or anticoagulant therapy was administered to avoid increased intracranial bleeding.
Protein C, protein S, and antithrombin III activity were normal for age. Anticardiolipin antibodies and lupus anticoagulant were negative; plasma homocysteine level was normal. D-dimer and factor VIII activities were elevated – 9980 ng/mL (normal for age <500 ng/mL) and 306% (50–120%), respectively; activated protein C resistance ratio was 1.98. Genetic tests confirmed heterozygosity for factor V Leiden (FVL; A1691G) and for TC677 methylenetetrahydrofolate reductase (MTHFR) polymorphism. No prothrombin gene (G2010A) mutation was found.
On day 60, the condition of the neonate deteriorated, showing anemia, thrombocytopenia, and blood in the urine. A thrombus in the right renal vein with progression into the inferior vena cava was diagnosed. The neonate was treated with LMWH at a dose of 1.125 mg/kg every 12 h, adjusted to achieve anti-factor X activity of 0.5–1. There were no bleeding complications detected and complete recanalization of the renal vein and partial recanalization of the inferior vena cava were observed after 14 days of therapy. The right kidney became atrophic. Renal function was normal. Prophylactic LMWH was continued for 6 months.
SIP, which is typically found in the terminal ileum, occurs primarily in premature neonates with very low birth weight (VLBW) or extremely low birth weight (ELBW). Prevalence of SIP in neonates born with weight <1500 g ranges from 1.1% to 7.4%. SIP is most common in males and occurs during the first 2 weeks of life. Several risk factors have been associated with SIP: prematurity, placental chorioamnionitis, postnatal glucocorticoids, indomethacin, and infections . Two different groups have been observed – the “early” age group: neonates who develop SIP before the third day of life; the etiology and pathogenesis are not well understood, and exogenous risk factors are less frequent and the “late” or “postnatal risk” group: neonates who develop SIP between 7 and 10 days of age , potentially associated with extrinsic factors such as postnatal steroid and/or early indomethacin administration .
SIP and necrotizing enterocolitis (NEC) are gastrointestinal complications that typically occur in premature neonates; their epidemiological and clinical differentiation is supported by the Pediatrix Medical Group data. SIP histopathology is associated with robust mucosa, with or without submucosal hemorrhage, and segmental/focal necrosis or absence of muscularis externa. Mucosal necrosis is a hallmark of NEC .
Thrombosis is uncommon at pediatric ages beyond the neonatal period. Critically ill neonates present the largest patient population suffering from thromboembolism during childhood. The reported incidence of symptomatic neonatal thrombosis is 2.4/1000 admissions to the neonatal intensive care unit, excluding stroke (Canadian registry) , and 0.51/10,000 live births (German registry) .
Over 90% of pediatric thrombotic events relate to underlying medical conditions, mainly central venous lines; FVL is considered the most frequent genetic risk factor related to venous and arterial thrombosis [5, 6]. Increased incidence of thromboembolic events is expected due to aggressive therapeutic interventions and improved survival of preterm neonates. Neonatal thrombosis is associated with high morbidity and mortality.
Several studies have assessed the incidence of genetic or acquired prothrombotic factors among patients with SIP and NEC. These studies failed to demonstrate a significantly high incidence of thrombophilia in those patients; one patient with NEC showed resistance to activated protein C and suffered from mesenteric vein thrombosis . The prevalence of genetic prothrombotic markers (including FVL) was evaluated in 166 preterm neonates and no association with the incidence of neonatal complications (including NEC) was found; the prevalence and severity of perinatal complications were similar among neonates with and without thrombophilia. Two patients with NEC were found to have thrombophilia .
A large study involving 1179 VLBW neonates investigated the association of hemostasis gene variants with perinatal outcome and complications. For NEC, the frequency of FVL was 4.4% vs. no FVL in 3.1% (P=0.68), and for intestinal perforation, 6.7% vs. 1.8%, respectively (P=0.068) , showing the association between SIP and FVL in a borderline statistically significant trend.
Our case report fits into the “early” SIP group, with intrinsic neonatal risk factors playing an important role in the pathogenesis. We observed the clinical features of SIP – early age of presentation, lack of enteral feeding and no intestinal pneumatosis, and the histopathological characteristics of both NEC and SIP.
We hypothesize that the neonate’s genetic tendency to thrombophilia – resistance to activated protein C caused by the FVL mutation – combined with exogenous risk factors contributed to the pathogenesis of the intestinal injury. The two subsequent major thrombotic events suggest an inherent thrombotic risk factor; the presence of capillary fibrin thrombus in the pathology sample, together with elevated D-dimer and high factor VIII activity, support this hypothesis.
A screening for thrombophilia should be considered in SIP cases, as it may be an additional factor in the pathogenesis of neonatal intestinal injury. If SIP proves to be a thrombophilic complication, therapeutic interventions could change, for example, by considering secondary prophylactic anticoagulant therapy, potentially preventing subsequent thrombotic events with possible catastrophic outcomes. Further investigations are required.
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The authors stated that there are no conflicts of interest regarding the publication of this article.
©2014 by Walter de Gruyter Berlin/Boston