Discussion
CRP in the healthy pregnant women in our study was substantially higher
than in most non-pregnant adults. Using a pregnancy-specific RI improved
the overall diagnostic accuracy for infection compared to the existing
non-pregnant RI, conferring a particular improvement in excluding
infection in healthy women without reducing the sensitivity materially.
The RIs for CRP were similar in all trimesters with only a small
reduction as pregnancy progressed.
The RIs reported in guidelines and large studies of CRP vary
substantially, e.g. ≤7 mg/L in the UK,10 and ≤10 mg/L
in the US and Australia.18, 19 The unmet need for an
established pregnancy-specific RI creates diagnostic uncertainty, which
risks clinicians disregarding elevated CRP results, or making
unnecessary interventions (e.g. iatrogenic delivery). Our study supports
using a relatively high upper reference limit for CRP in pregnancy, as
this predicted infection with a much greater degree of accuracy than the
existing guidance.
The value of using CRP for diagnosing chorioamnionitis through intact
membranes is unclear, but there is a growing body of evidence supporting
its use in pregnant women with preterm prolonged rupture of membranes. A
2018 meta-analysis reported pooled sensitivities and specificities of
69% and 77%, respectively, although the upper reference limits for CRP
varied widely (3-18.7 mg/L).20 The results of our
study are similar to those of a more recent review which reported
sensitivities and specificities of 59% and 83%, respectively, using an
upper reference limit of 20 mg/L.21 Studies of other
blood biomarkers have reported better diagnostic accuracy when using
pregnancy-specific reference intervals: Girling, et al. reported
that aspartate transaminase, alanine transaminase, bilirubin and gamma
glutamyl transferase were lower in pregnancy, and that using these
pregnancy-specific RIs significantly improved disease detect rates.22
Adipose tissue is known to mount an immune response to
overnutrition,23 which is likely to drive the elevated
levels of CRP seen in the overweight women in this study, as CRP is not
able to discriminate between infection and other causes of inflammation.
The relationship between obesity and CRP is well documented in
pregnant24, 25 and non-pregnant
populations,26 but partitioned RIs for CRP are not
routinely used in clinical practice. We propose that stratifying CRP
results according to BMI would be challenging for routine use, but we
have presented them for consideration. CRP in women pregnant with male
babies was slightly higher than those with female babies, which was
statistically significant at the 1% level in the second trimester only;
we include this as it may be useful for consideration in future
research.
Strengths and weaknesses
Ours is the largest study identified to have investigated CRP in
pregnant women, and its associations with BMI and gestational age. Our
study may include some women with undiagnosed gestational diabetes, as
screening is not universal in the UK, but it is uncertain whether this
is independently associated with CRP after adjustment for
BMI.27 Most women in our study were white so we cannot
comment on differences in CRP between ethnic groups.
Diagnostic accuracy studies in pregnancy are challenging without a gold
standard for maternal infection. Our approach is consistent with
previous studies on histological chorioamnionitis20and we have augmented this with microbiological and microscopic data. We
acknowledge that the timing of some of the CRP samples (postnatal) may
over-represent the antenatal CRP at the actual time of amniocentesis
(such procedures are not usually performed in those with a very high
CRP). However, within the limits of this pragmatic retrospective study,
it should not preclude comparing the two reference limits evaluated
here.
Conclusions
Concentrations of CRP are sufficiently elevated in pregnant women that
pregnancy-specific RIs should be used to improve diagnostic accuracy. We
have defined and evaluated a new RI for CRP in healthy pregnant women,
with specific considerations for characteristics that may modify its
limits.