# Mind the “CRP gender gap”! sex differences in CRP evolution over time in neonatal sepsis: a monocentric retrospective cohort study

## TL;DR

The study finds that female neonates show a faster initial rise in CRP levels compared to males, but no differences in peak or decline rates, suggesting sex influences immune response patterns in early life.

## Contribution

This is the first study to analyze sex differences in CRP kinetics during neonatal sepsis using a piecewise regression model.

## Key findings

- Female neonates had a faster CRP rise in the first 12 hours of life compared to males.
- After 12 hours, female neonates showed a slower increase in CRP levels.
- No significant sex differences were observed in CRP peak levels or decline rates.

## Abstract

C-reactive protein (CRP) is a readily available test widely used to assess neonatal sepsis (NS). In children with sepsis or other infectious conditions, CRP is more likely to be higher in females than males, however, evidence is lacking on sex differences in CRP in the neonatal population. This study aims to describe sex differences of CRP evolution in the ascending and decreasing phase after its peak in neonates with likely NS.

This is a monocentric retrospective cohort study conducted at Etterbeek-Ixelles Hospital in Brussels. We included all neonates born in the facility between January 2017 and December 2022 who received antibiotics in the first 72 hours of life. Patients whose CRP concentrations remained under 10 mg/L were excluded. To describe the ascending kinetics of CRP and its logarithm for male and female neonates, we fitted a piecewise linear mixed-effects regression model with birth considered as time zero and one knot at 12 hours of life. We used a linear mixed-effects regression model with CRP peak considered as time zero to describe CRP’s descending kinetics and its logarithm for male and female neonates.

We included 506 neonates (60.1% male and 39.9% female). CRP concentration in the first 12 hours of life doubled every 3.2 and 2.8 hours, respectively, in males and females, with female neonates having a statistically significant faster rise of base 2 logarithm of CRP (+0.04 log2 mg/L/hour 95% CI= +0.01 +0.07). After 12 hours of life, CRP doubled every 6.5 and 8.6 hours, respectively, in males and females, with female neonates having a statistically significant slower rise of base 2 logarithm of CRP (-0.039 log2 mg/L/hour 95% CI= -0.02 -0.06). After its peak, CRP decreased by half every 31.1 and 30.9 hours, respectively, for males and females. No statistically significant sex differences were found in CRP peak or decline.

In neonates of both sexes with likely but unconfirmed NS, CRP seems to increase, reach a peak, and then decrease, following a logarithmic pattern. Before antibiotic treatment, female neonates in our population showed an earlier increase in CRP levels, with no difference in peak CRP levels.

The online version contains supplementary material available at 10.1186/s13293-026-00841-9.

C-reactive protein (CRP) is produced by the liver during inflammation and is widely measured to assess a range of infectious and inflammatory conditions. In children, CRP levels are often higher in females than in males, but data on sex differences in the neonatal period (0–28 days) are limited. This study aims to characterize sex differences in CRP concentrations among neonates with suspected infection. We examined both phases of CRP kinetics: the rising phase, reflecting the host response before treatment, and the declining phase, reflecting recovery following antibiotic therapy. A total of 506 neonates were included in the study (304 male neonates and 202 female neonates). Before treatment, female neonates showed an earlier increase in CRP, although peak levels did not differ significantly between sexes. In the first 12 hours of life, CRP doubled every 3.2 hours in males and every 2.8 hours in females, indicating a faster rise in females. After 12 hours, the doubling time was 6.5 hours in males and 8.6 hours in females, suggesting a slower rate of increase in females. No sex differences were observed in the declining phase of CRP. Our findings highlight that immune responses differ by sex even in the neonatal period. Clinicians should be aware that sex is a relevant factor when interpreting standard laboratory markers such as CRP.

The online version contains supplementary material available at 10.1186/s13293-026-00841-9.

Compared to male neonates, female neonates of our population showed a statistically significant earlier rise in C-reactive protein (CRP) levels before antibiotic treatment.

CRP probably increases following a logarithmic pattern with concentrations of the first 12 hours of life doubling every 3.2 hours for male neonates and every 2.8 hours for female neonates. Therefore, the speed of exponential growth decreases after the 12th hour of life with a doubling time of 6.5 hours for male neonates and 8.6 hours for female neonates.

Despite earlier rise in CRP level for female neonates, we found no significant difference between sexes in CRP peak levels.

After reaching its peak, CRP decreases following a logarithmic pattern, dropping by half every 31.1 hours in males and 30.9 hours in females, with no statistically significant difference between sexes.

The online version contains supplementary material available at 10.1186/s13293-026-00841-9.