Persistent High CRP Levels in Nonseptic Asphyxiated Newborns: A Report of Three Cases

Introduction: Hypoxic-ischemic encephalopathy (HIE) is the most serious outcome of perinatal asphyxia and therapeutic hypothermia (HT) is its only accepted effective treatment, reducing neuronal damage and ischemia reperfusion injury. As previously reported hypothermia interferes with leukocyte functions and retards the release of proinflammatory cytokines.

Empirical antibiotic treatment is routinely performed in newborns undergoing hypothermia, its duration depending on blood cultures and C-reactive protein (CRP) levels. Some noninfectious conditions may complicate the interpretation of laboratory findings, since shock, meconium aspiration syndrome, fetal distress, maternal fever, and intraventricular hemorrhage may cause elevation of CRP levels without infection. Literature data about CRP levels in HIE newborns are scanty, and the question of whether CRP is elevated in nonseptic HIE infants remains open.

Levene and Evans reported high CRP levels in 68% of severe HIE patients (Sarnat’s grades 2 and 3) in the first 3 days of life (DOL).¹ Okumuş et al compared a cohort of patients undergoing hypothermia with a control group of asphyxiated newborns who did not meet hypothermia criteria and found significantly higher CRP levels in the hypothermia group. They suggested that hypothermia might be associated with CRP elevation, reaching the peak on day 4 and gradually decreasing to a normal range at 12.4 ± 7.7 DOL.²

Results: We report late increase of CRP levels in the absence of signs of sepsis/infections in three full-term newborns who suffered intrapartum hypoxic-ischemic insults ([Fig. 1]). They were born by urgent cesarean section because of pathological cardiotocography. Nobody had perinatal risk factors for infection.

Patient A (GA 38⁺⁶ weeks, BW 3,200 g, Apgar score 1/6/10) had umbilical artery base excess (BE) of −14.2; Sarnat grading was 2 to 3 and cerebral function monitoring (CFM) was pathological. Hypothermia was started and the infant underwent phenobarbital treatment following seizures. On the fourth and fifth DOL patient’s right arm was found paler and colder than the contralateral, although Doppler study did not show any arterial occlusion. CRP levels increased in the 5th DOL and reached a peak on the 11th DOL. The elevation lasted 3 weeks and gradually decreased independently from antibiotic therapy.

Patient B (GA 39⁺⁵ weeks, BW 3,680 g, Apgar score of 0/3/6) had umbilical artery BE of −22.1; amniotic fluid was meconium stained. Sarnat grading was 1 and CFM was normal. The patient did not undergo HT. CRP levels increased on the 5th DOL, reached the peak on the 7th DOL, and normalized on 11th DOL.

Patient C (GA 38⁺⁵ weeks, BW 3,412 g, Apgar score 1/7) had umbilical artery BE of −16.3. Asphyxia was caused by severe anemia due to fetal–maternal transfusion. Sarnat grading was 2 and CFM was pathological. Hypothermia was started and the infant underwent phenobarbital and midazolam treatment following seizures. During clinical course, CRP elevated twice: at 10th DOL probably due to LOS (Staphylococcus epidermidis) and at 28th DOL without any clinical or laboratory signs of infection.

In all patients, blood cultures were negative at birth and at the time of CRP elevation (except for the first peak in patient C). Urine and LCR cultures, as well as procalcitonin, were negative. Virological, immunological, and radiological investigations were negative too. No patients had clinical signs of infection and variation in CRP level seemed to be independent from antibiotic treatment.

Conclusion: We hypothesize that high CRP levels in some HIE patients is unrelated to infection. Differently from previous reports, we did not find a clear relationship between high CRP levels and the grade of asphyxia (Sarnat 2–3 vs. Sarnat 1),¹ neither with hypothermic treatment,² since one patient did not have HT. One patient of our series showed a transient regional disturbance of microcirculation, as previously described by Fredly et al in HIE patients with high CRP levels.³ Mechanism of CRP increase in HIE newborns is still unknown and further data are needed to investigate this relationship, to avoid unnecessary antibiotic treatments and developing of antibiotic resistant bacteria.

Fig. 1 Persistent high CRP levels in nonseptic asphyxiated newborns.