PVT was diagnosed in a high proportion (27%) of near/full term included in the study, and even higher (36%) in infants cooled for HIE. Consistently, after adjustment for confounding co-variates, PVT was found to be significantly more frequent in infants treated with CTH for HIE compared to infants unexposed to HIE. To our knowledge, this study is the first one reporting the incidence of PVT in cooled infants.
Umbilical vein catheterization is considered as the most important risk factor for neonatal PVT development [4, 6, 7, 10–12]. In our study, the incidence of UVC-associated PVT was 27%, lower than other reported series [4, 7, 10, 12]. Discrepancy between reported incidences can be related to population characteristics, diagnosis delay, and variability due to spontaneous recovery and asymptomatic course in most cases. The lower incidence in our study may be related to the exclusion of very low birthweight or premature infants and potential variation in the severity of illness.
Similarly, to previous studies and consistently to anatomic configuration [7, 10, 21], we found that most of UVC-related PVT were localized in the left portal vein branch (95%). Position of catheter tip and prolonged catheterization have been identified as risk factors for neonatal PVT [7]. However, in the present study, the most appropriate position for an UVC tip position, considered as the junction of the inferior vena cava and right atrium, was reported in 58% of cases and in 62% of controls, and this difference was not statistically significant in univariate analysis. In contrast, the duration of UVC was found associated with the risk of PVT, both in unadjusted analysis and multivariate models.
Theoretically, reduction in heart rate and blood flow during CTH could increase the risk of venous thrombosis, as demonstrated for cerebral thrombosis [13]. Conversely, there are also evidences about risks of bleeding and disseminated intravascular coagulation in neonates with HIE, potentiated by CTH. Competitive alterations of hemostasis (i.e. bleeding versus thromboembolic events) can be both present in asphyxiated infants and CTH may potentiate microvascular thrombosis formation [24]. Our data support this hypothesis, although CTH did not correlate with a particular location or with the severity grade of PVT.
HIE has been identified as a risk factor for neonatal thrombosis (similarly to sepsis, dehydration, or metabolic acidosis [10]), in observational studies [21, 22] and in a recent review [23]. In the present study, metabolic acidosis, a constant indicator for HIE was not found to be significantly associated with PVT. All infants with HIE included in our study were treated by CTH, according to the French guidelines [17]. While clear benefits of CTH in HIE are now widely recognized, a causal link between PVT as a potential side effect of either HIE (the disease itself) or CTH (treatment of this disease) remains to be confirmed. However, because CTH is only initiated in infants with HIE in NICU, this treatment should lead to a systematic screening for PVT.
The other reported risk factors for neonatal PVT reported in the literature include transfusion of blood products through the UVC, HIE, dehydration, polycythaemia, sepsis, congenital cardiac malformation and maternal diabetes [4, 7, 21–24]. Here, we found no significant differences for maternal diabetes, birth weight, perinatal metabolic acidosis, Apgar score, hemoglobin at birth, hemodynamic instability and respiratory distress, and EOS. According to our local guidelines, blood products are not administrated through the UVC, reason for excluding this risk factor in our description, as well as the condition of thrombophilia, as its role in neonatal PVT remains controversial.
All babies included in our study were asymptomatic for PVT, as reported previously [4, 21]. Consistently with our results, thrombocytopenia was reported as a relatively common sign at diagnosis [4].
Clinical relevance of anticoagulation for PVT remains still unclear since a significant proportion resolve spontaneously [5, 25]. Low-molecular-weight heparin was often used to treat PVT in our cohort. Because our study was not designed to describe the effect of this therapy on PVT evolution, definitive recommendations cannot be made.
A limitation of this study is its relatively small sample size (57 cases). Although comparable with most previous studies, further prospective investigations to confirm associations between PVT and HIE with and without CTH is needed. The retrospective study design and the lack of information on long-term follow up, including US control or effect of anticoagulant therapy, are also other substantial limitations.
In conclusion, left portal venous thrombosis is often observed also in nearly term neonates who need an UVC placement and asphyxiated cooled infants appear particularly at risk to develop PVT.
Pending further confirmation in a larger population, our study suggests to reduce the duration of UVC placement as short as possible, and to screen for PVT all patients cooled for HIE.