Hypoxic-ischemic brain injury that occurs during the perinatal period is one of the most recognized causes of severe, long-term neurological deficits in children. 30
However, the concept that cerebral palsy is due only to acquired insults such as perinatal asphyxia has been fundamentally challenged in the past decade. The current view is that the vast majority of injuries are the result of interplay between several risk factors such as genetic background, acute intrapartum hypoxia, excitotoxicity, oxidative stress, sepsis and an exacerbated inflammatory fetal and placental host response. 30,31
Discerning among these factors is important not only when formulating antenatal preventative or therapeutic strategies to avert cerebral palsy but also within medico-legal contexts. In regard to the latter, clinical practice guidelines indicate the importance of evaluation of umbilical cord blood gases and acid-base status of the premature neonate at the time of birth in order to document or exclude possible intrapartum hypoxic events.32
Furthermore, exclusion of other identifiable causes (i.e. trauma, coagulation disorder, or infectious or genetic conditions) is vital before declaring an anoxic intra-partum event as the definitive cause of poor neuro-developmental outcome.
A series of studies formally addressed the question of whether by using non-invasive clinical tests, septic fetuses can be accurately recognized in utero
While some felt that fetal breathing, biophysical profile, AF index, and non-stress test were useful tools for evaluating fetuses at risk for infection, 3,9,10
others disagreed. 11,34,35
The differences in opinion among authors may be due to the retrospective nature of most of the above studies, a wide variability in the time interval between the assessment of the FHR-MP and delivery of the fetus, along with the inability to simultaneously integrate in one project the information pertaining to FHR-MP, inflammatory status of the AF and placenta, and EONS. Given the above limitations, the lack of consensus in the literature, and the significant changes in the NICHD recommended guidelines for interpretation of the FHR, we felt compelled to readdress the question by analyzing a prospective cohort of fetuses while standardizing variables (such as the times of FHR assessment) and interval to delivery in order to minimize bias. In this context, we found that fetuses with severe intra-amniotic inflammation are more likely to have some, but not all FHR-MPs altered. Interestingly the most specific changes (increased FHR baseline compared to those without inflammation, and a non-reactive, non-reassuring FHR-MP) were those at the time of IEV due to an increased proportion of fetuses exhibiting non-reactive and/or non-reassuring patterns closer to delivery. However, the increased inflammatory status of the AF cannot independently explain the possible association between an abnormal FHR-MP and EONS.
It was hypothesized that “sensitization” of the umbilical cord blood vessels by the inflammatory cytokines alters the vasomotor response to mechanical compression which may occur secondarily to uterine contractions or fetal movement.3
We analyzed the FHR-MP in regard to the presence or absence of histological funisitis (grade 2–4). We determined that an advanced grade of arteritis and phlebitis is associated with a higher FHR baseline and a non-reactive, non-reassuring FHR-MP at the time of IEV. The finding of a similar distribution of uterine contractions among groups at the time of IEV but also at AEV and DEV suggests mechanical compression of the cord is not solely responsible for an abnormal FHR-MP and provides support for the above hypothesis. Conversely, all episodes with fetal tachycardia occurred in the context of severe intra-amniotic inflammation, infection and funisitis and in most of the cases in the absence of maternal fever. This suggests that in certain clinical scenarios evaluation of the intra-uterine environment may be warranted even in the absence of maternal signs or symptoms of chrioamnionitis.
Recognition of EONS is difficult 36
and clinicians routinely over treat neonates with antibiotics, under the assumption that an infant is more likely to suffer if infection is not diagnosed rather than if the infant is treated unnecessarily. Furthermore, 75% of neonates in our study have also been exposed to antibiotics antenatally. Therefore, the small number of neonates with proven sepsis should not come as a surprise. To overcome this specific difficulty, neonatologists often have to rely on standardized hematological criteria to diagnose EONS.26,27
Because none of the prior studies that analyzed FHR-MPs in relationship with perinatal sepsis have assessed intra-amniotic inflammation directly, it was important for us to analyze the relationships of the various FHR-MP, placental inflammation and EONS separately. We show that the only FHR-MP at the time of IEV significantly associated with EONS is a non-reassuring FHR. Although the odds ratio of a non-reassuring FHR-MP at the time of IEV to predict EONS was higher than that of any other FHR element taken into consideration, this pattern was neither a sensitive nor a highly accurate test to predict EONS antenatally. Our analysis determined that the two fetuses with proven sepsis by positive blood cultures and most of the fetuses diagnosed with EONS using hematological findings had in fact a reassuring non-stress test at the time of IEV. Because a non-reassuring FHR is a clinical indicator for rapid delivery of the fetus, the clinical utility of a non reassuring non-stress test can, at best, increase the level of clinical awareness that a fetus with EONS may be born but it cannot be used at this time to dictate whether or not neonatal antibiotic treatment should be instituted at the time of delivery. Since our data indicate that more than half of fetuses studied showed at some point an altered FHR-MP and none in the context of abnormal umbilical artery pH values, it can only underscore the importance of documenting the acid base status at delivery in instances with abnormal FHR-MP especially if amniocentesis results are not available for reference.
Finally, we have to acknowledge the persistence of several biases inherent to the population analyzed. The exclusion criteria for amniocentesis biases to the null (i.e. we may have missed patients presenting with abnormal FHR-MP requiring immediate delivery). Conversely, our restriction of the analysis to women delivering within 48 hours from amniocentesis biases away from the null given the higher prevalence of intra-amniotic infection managed with indicated delivery in this subgroup. Previous studies have shown that steroids can cause transient but profound suppression of FHR parameters, which can mimic distress.37
Our analysis demonstrated that steroid exposure was indeed associated with non-reassuring FHR-MPs at both AEV and DEV. This may explain the increased frequency of abnormal FHR-MP at these later times irrespective of intra-amniotic inflammation.