**8. Do special subpopulations need special CRP reference values?**

Especially in the early neonatal period, many physiological and metabolic processes are in change and differ from every later moment in life. These changes affect several laboratory parameters as well and many reference values and serum kinetics substantially differ to later periods. [62]

Reliable reference values are crucial for obtaining an adequate diagnostic accuracy. Upper limits for CRP during the first days of life have mainly been established from uninfected but symptomatic neonates. The cut-off values reported in the literature range from 1,5mg/l to 20 mg/l with thus wide ranging sensitivities and specificities. [11, 63] The up to date most used upper limit for CRP during the first days of life of 10 mg/l has been established in 1987 by Mathers and Pohlandt. [28] One decade later, Benitz et al. evaluated CRP levels in 1002 episodes of suspected early onset sepsis and confirmed the value being an appropriate threshold level. [23]

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**10. References** 

Use of CRP in the first few days after birth is complicated by a nonspecific rise primarily related to the stress of delivery. [11, 45] This rise of CRP starts shortly after birth and peaks with 13 mg/l in term and 11 mg/l in preterm newborns during the second and third day of life, respectively. [44] These observations raise concern about the static cut-off value not reflecting the physiologic kinetics of CRP after birth. In view of the physiologic dynamics of CRP during the first days after birth and the influence of gestational age on its response to infection, it appears reasonable to reconsider this static cut-off value and evaluate the possible advantages of the introduction of dynamic reference values. However, the current literature lacks sufficient evidence to make recommendations for the use in clinical practice.
