This study provides evidence that placental pathology is more common in newborn infants with moderate or severe HIE than healthy controls. This study is in keeping with other studies that have compared placentae of infants with HIE and controls [7, 8, 10]. Several specific placental pathologies had an increased incidence in cases compared with controls, including HCA, FVM and DVM. This could indicate that these placental pathologies are either a direct cause of HIE or contribute to reduced placental reserve, resulting in earlier and more significant fetal decompensation in the setting of intrapartum HI.
The incidence of FVM was higher in infants with moderate or severe HIE compared with controls. This finding supports the results of other studies [7, 10]. There was also a higher incidence of FVM in cases without an ISE compared to those with an ISE (31% v 16%), although there were very small numbers and this was not statistically significant. This suggests that FVM may have a larger role in cases of unexplained HIE. Cases with FVM were more likely to demonstrate hyper-coiling compared with controls. Higher CI in cases could be a contributory factor to the development on FVM.
This study demonstrates an increased incidence of HCA in infants with HIE compared to healthy controls. The incidence of HCA in cases in this study is also higher than the incidence of HCA reported in a healthy population in others studies [8]. This has been reported in studies previously, including in a cohort study by Novak et al where they found HCA was more common in infants with HIE with an unexplained cause [11].
For cases in this study, fetal inflammatory response (FR) was present for 61% of cases affected by HCA. Bingham et al also found cases with HCA had a much higher incidence of FR than controls with 100% of their cases with HCA having FR, although they did report a higher incidence of HCA in their control group compared to the current study[10]. This may be due to selection bias within their control group which included infants admitted to NICU for a reason other than HIE, and likely does not represent a control cohort of healthy term infants. McDonald et al and Mir et al conducted cohort studies for infants with HIE and found that HCA, particularly HCA with FR, was associated with encephalopathy and an increased severity of encephalopathy [12, 13]. The HEAL trial found 39% of their cohort had HCA [14]. Naisell et al performed a case-control study and found no association between HIE and HCA, however their study only had 41 cases with placental findings and included infants with mild, moderate and severe HIE. Details of the number of each grade of HIE and their placental pathologies were not included in their report. Placental findings in infants with mild HIE may differ from infants with moderate or severe HIE. An inflammatory response on the fetal side of the placenta implies that the fetus was affected by inflammation. This is more commonly known as Fetal Inflammatory Response Syndrome (FIRS) [15]. FIRS is associated with increased neonatal mortality and neonatal, childhood and adult morbidity [16–18]. HCA, particularly in the setting of FR, has likely led to a preconditioning of the fetal brain. The inflammation may have a direct effect on the developing fetal brain and/or act as a primer for fetal brain injury in the setting of intrapartum HI. FIRS can lead to impaired perfusion, oxygen delivery and/or disseminated intravascular coagulation, leading to micro-thrombi in the capillaries, culminating in hypoxic tissue [19]. This process may increase tissue vulnerability to reduced delivery of oxygen in the setting of labour and delivery, even if HI is within the limits of a typically progressing intrapartum course. This may explain the pathogenesis of HIE for some infants with a seemingly normal intrapartum course.
DVM was also significantly increased in cases. Some studies have found no association between DVM and HIE [10, 13, 20]. However, Harteman et al looked at the relationship between brain injury on MRI and placental findings in HIE. They found placental immaturity to be associated with white matter brain injury [21].
In contrast, MVM was more common in controls than cases but this was not statistically significant. Some studies have found features of MVM to be associated with HIE [10, 13], in contrast to the findings in this study. Unfortunately, MVM has not been routinely reported in many placental pathology studies on HIE so it if difficult to determine if this study is an outlier in this respect or not. This study did find that where MVM was present in cases, birth weight was lower than in all cases and lower than controls with MVM. This may suggest that where MVM is present in a fetus, it could be contributing to suboptimal fetal growth and potentially impair tolerance of labour.
VUE was also more common in controls than cases. In studies where VUE has been reported, it was not found to be associated with HIE [5, 8, 10, 13]. Controls in this study were born during a time of the COVID-19 pandemic, and pregnancies may have been exposed to either COVID-19 infection and/or COVID-19 vaccination, both of which lead to an immune response in the mother. COVID-19 infection in pregnancy has been associated with inflammation of the placenta, termed ‘COVID placentitis’ [22]. It may be that this control group developed VUE from a COVID-19-associated immunological response. The rate of VUE in healthy pregnancies is reported in the literature to be between 6 and 33% [23], therefore this control group could also be reflective of a normal population.
Strengths
A major strength of this study is that it reports on a good sample size of cases with moderate or severe HIE compared with other studies on placenta pathology in HIE. It also includes a control group of neurologically healthy term infants without medical illness or clinical indication for placental assessment.
Limitations
Recruitment of controls was limited by the capacity of the histopathology department to process the additional workload for placenta analysis and were collected over a period of one year. It was not possible to blind the reviewer to whether the placenta slides were from a case or control. Case placenta slides were archived slides that were retrieved from storage. Control placenta slides were stored on site until they were reviewed. The reviewer was blinded to the clinical details of the cases. Due to resource limitations, we were unable to have a second reviewer to analyse the placentae leading to an inability to determine the presence of any bias within the reporting.
This case-control study provides evidence for differences in placental histology between infants with moderate or severe HIE and a convenience sample of healthy controls. Infants with HIE had a higher incidence of pathology overall, and specifically for HCA, FVM and DVM. This suggests that placental pathology may be a risk factor for poor tolerance of labour and/or is likely to be a contributing factor in the pathogenesis of HIE, particularly in the absence of an ISE. Further research is required to further delineate the role of the placenta in the pathogenesis of HIE.