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\begin{document}

\title{Pregnancy-specific reference intervals for C-reactive protein improve
diagnostic accuracy for infection: a cross-sectional and diagnostic
accuracy study}



\author[1]{Samuel Dockree}%
\author[1]{Jennifer Brook}%
\author[1]{Tim James}%
\author[1]{Brian Shine}%
\author[1]{Lawrence Impey}%
\author[2]{Manu Vatish}%
\affil[1]{Oxford University Hospitals NHS Foundation Trust}%
\affil[2]{University of Oxford}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Objective To define a trimester-specific reference interval for
C-reactive protein (CRP) in healthy pregnant women, and to evaluate its
accuracy for diagnosing infection. Design Retrospective cross-sectional
and diagnostic accuracy study. Setting Tertiary hospital in Oxford, UK.
Population Development cohort: 315 pregnant women from the Oxford
Pregnancy Biobank with uncomplicated pregnancies, with longitudinal
sampling in each trimester. Evaluation cohort: 50 pregnant women with
suspected chorioamnionitis. Methods and main outcome measures We
calculated a 95\% reference interval for CRP in each trimester and
evaluated its diagnostic accuracy for infection compared to that from
current guidance ([?]7 mg/L). Results Of the 315 healthy pregnant women in
our study, concentrations of CRP were substantially higher than those in
most non-pregnant populations. The reference intervals in each trimester
were similar, with an upper reference limit of 18 mg/L. CRP increased
log-linearly with body mass index in all trimesters (p\textless{}0.001).
The sensitivity and specificity of CRP for diagnosing chorioamnionitis
were 80\% and 86\%, respectively. The overall diagnostic accuracy using
the pregnancy-specific reference interval was significantly greater than
that of the existing standard (p=0.002). Conclusions A
pregnancy-specific reference interval for CRP should be used to optimise
diagnostic accuracy for infection in pregnant women. Chorioamnionitis
was used as example of a localised infection with well-defined outcomes,
but pregnancy-specific upper reference limits for CRP should be
considered in any clinical setting including pregnant women.%
\end{abstract}%



\sloppy


\section*{Tweetable abstract}

{\label{tweetable-abstract}}

Using a pregnancy-specific reference limit for C-reactive protein
significantly improves diagnostic accuracy for infection.

\section*{Introduction}

{\label{introduction}}

It is increasingly clear that maternal deaths from infections are more
common than was previously appreciated.\textsuperscript{1} The burden of
obstetric and non-obstetric infections, which is particularly profound
in low- and middle-income countries,\textsuperscript{2} has been
addressed in international efforts to prevent maternal
mortality,\textsuperscript{3} but sepsis remains the third commonest
cause of maternal death worldwide.\textsuperscript{2} The availability
of accurate and affordable diagnostic tools is an important prerequisite
for diagnosing infection in modern clinical practice, but they can be
prohibitively expensive, and have rarely been validated in pregnant
populations.\textsuperscript{4, 5} This prompts us to re-evaluate
existing tests, and to consider if we can optimise them for clinical
practice.

C-reactive protein (CRP) is an acute phase reactant that rises in
response to inflammation, and it is most commonly used to investigate
suspected infection. Concentrations of CRP are low in most healthy
individuals\textsuperscript{6} but the upper reference limits have been
variably reported between 3 and 10 mg/L.\textsuperscript{7} Pregnancy is
associated with immune cell activation and
proliferation,\textsuperscript{8} and it has been reported that CRP is
elevated in pregnant women from early in the first
trimester,\textsuperscript{9} although the extent of this is unclear.
Despite this, current guidelines on suspected sepsis by the Royal
College of Obstetricians and Gynaecologists recommend using an upper
reference limit of 7 mg/L,\textsuperscript{10} which is similar to most
non-pregnant standards.

The existing reference intervals (RIs) for CRP are usually derived from
non-pregnant populations and often include individuals who are
significantly older than most healthy pregnant women. By making
comparisons to RIs from an unrepresentative population, the diagnostic
accuracy of the test may be compromised. Importantly, pregnancy is a
dynamic physiological state associated with progressive, marked plasma
expansion and altered hepatic and renal function,\textsuperscript{11} so
it cannot be assumed that concentrations of CRP are stable throughout
pregnancy. Establishing robust, population-specific RIs is essential for
using diagnostic biomarkers safely in clinical practice but, unlike
other tests,\textsuperscript{12} there is no established RI for CRP in
pregnant women. To address this, we undertook a cross-sectional study of
315 healthy pregnant women to estimate an RI for CRP in uncomplicated
pregnancy and evaluated its diagnostic accuracy for chorioamnionitis, as
an example of an infection.

\section*{Methods}

{\label{methods}}

\subsection*{Development cohort}

{\label{development-cohort}}

We identified potentially eligible participants from the Oxford
Pregnancy Biobank between April 2009 and April 2010 and examined them
against our inclusion criteria to obtain an objectively healthy
population of pregnant women from which to estimate RIs. The Oxford
Pregnancy Biobank was a prospective study of pregnant women in Oxford,
UK (REC 07/H0607/74), in which pregnancy-specific data were recorded in
each trimester and after delivery. A maternal blood sample was taken and
stored from the first, second and third trimesters at
10-14\textsuperscript{+6}, 18-23\textsuperscript{+6}, and
31-38\textsuperscript{+6} weeks, respectively.

The inclusion criteria for our study were adult pregnant women ([?]18
years old) with uncomplicated pregnancies. We excluded women with
chronic hypertension or diabetes mellitus, and women whose index
pregnancy was complicated by gestational hypertension (blood pressure
[?]140/90), pre-eclampsia (hypertension with proteinuria), HELLP syndrome
(haemolysis, elevated liver enzymes, low platelets), acute fatty liver
of pregnancy, gestational diabetes (abnormal oral glucose tolerance
test) or obstetric cholestasis (pruritis with bile acids
\textgreater{}14 \selectlanguage{greek}µ\selectlanguage{english}mol/L).

\subsection*{Analysis}

{\label{analysis}}

Plasma CRP was measured using an immunoturbimetric method on the Abbott
Architect C16000 analyser (Abbott Laboratories Ltd, Maidenhead, UK)
after a single freeze-thaw cycle (-80\selectlanguage{ngerman}°C). Inter-assay imprecision
expressed as CV, \% was 5.4\% at 1.6 mg/L, and 1.0\% at 53.6 mg/L,
imprecision was 1.02\%. The lower detection limit was 0.2 mg/L.

\subsection*{Statistics}

{\label{statistics}}

Data on CRP in each trimester were approximated to a normal distribution
using the natural logarithmic transformation:

\begin{equation}
f\left(x\right)=ln(x-k)\nonumber \\
 \end{equation}

where \emph{k} was calculated to minimise skewness. Outliers were
identified using Horn's\textsuperscript{13} interpretation of the method
described by Hoaglin, \emph{et al.} \textsuperscript{14} Data were
binned into groups of maternal age and BMI, and participants were
excluded in whom CRP was more extreme than 1.5 times the interquartile
range above or below the 3\textsuperscript{rd} or 1\textsuperscript{st}
quartiles, respectively. The transformations were reapplied after
excluding outliers and Shapiro-Wilk tests were used to confirm the
distributions.

RIs were calculated for each trimester, equating to the
2.5\textsuperscript{th} and 97.5\textsuperscript{th} percentiles derived
from the mean and standard deviation, and the reference limits were
presented with their respective 90\% confidence
intervals.\textsuperscript{15} One-way ANOVA or Student's t-tests were
used to investigate differences in CRP according to groups of maternal
age, BMI, mean arterial pressure (at booking), ethnicity, and fetal sex.
Participants with missing data in any variable were excluded from
subgroup analyses as the frequency of missing data was
minimal.\textsuperscript{16} We ran a multivariate linear regression
model to investigate the association between CRP and BMI, and
investigated partitioning the RIs using the method described by
Lahti,\emph{et al} .\textsuperscript{17} Summary statistics for normally
distributed data are presented as the mean and standard deviation, or
otherwise as frequencies and proportions. Statistical significance was
assumed at the 5\% level, or at the 1\% level for subgroup analyses.

\subsection*{Evaluation cohort}

{\label{evaluation-cohort}}

We evaluated the diagnostic accuracy of the new upper reference limit
for CRP for detecting infection, using chorioamnionitis as a
well-defined example of infection. We retrospectively identified a
subset of 50 consecutive women who had undergone amniocentesis for
suspected infection, and extracted the maternal serum CRP to calculate
the sensitivities, specificities, positive and negative predictive
values, and areas under the receiving operator curves for infection
using two reference limits:

\begin{itemize}
\tightlist
\item
  CRP [?]7 mg/L (derived from current guidance on suspected sepsis in
  pregnancy)\textsuperscript{10};
\item
  The gestation-specific reference limit estimated from the development
  cohort.
\end{itemize}

The overall diagnostic accuracy of the two reference standards was
compared using receiving operator curve (ROC) analysis. Chorioamnionitis
was defined as microbiological growth or microscopic evidence of
organisms in amniotic fluid, growth on a placental swab, and/or a
histological chorioamnionitis/funisitis if delivery occurred within one
week. Women with uterine contractions or evidence of another infection
were excluded. Where possible, CRP results were extracted from the same
day as the amniocentesis, or within 24 hours.

\section*{Results}

{\label{results-1}}

\subsection*{Participant
characteristics}

{\label{participant-characteristics}}

A total of 334 women were potentially eligible, of whom 19 (5.7\%) were
excluded as outliers; details on outliers are presented in Appendix S1.
Of the 315 women included in the development cohort, most were white
(93\%), had a normal BMI or were moderately overweight, and delivered at
full term (mean gestation 40.4 weeks). Most babies did not require
admission to the neonatal unit (98.1\%). On average, overweight women
([?]25 kg/m\textsuperscript{2}) had a significantly higher mean arterial
blood pressure and gave birth to heavier babies than women with a normal
BMI (\textless{}25 kg/m\textsuperscript{2}). Fewer than 2\% of data were
missing according to any characteristic. Data on participant
characteristics are summarised in Table 1.

\subsection*{Reference interval
development}

{\label{reference-interval-development}}

Trimester-specific reference intervals for CRP are presented in Table 2.

CRP was not associated with maternal age, mean arterial pressure or
ethnicity, but BMI was significantly log-linearly associated with CRP in
all trimesters (see Figure 1 and Appendix S2). CRP was marginally higher
in women pregnant with male babies than female babies, but this finding
was only significant in the second trimester. The statistical conditions
for partitioning the reference intervals for CRP by BMI were either met
or were marginal in all trimesters, using a cut-off of 25
kg/m\textsuperscript{2}, so an overall reference interval was used.
BMI-specific reference intervals are presented in Table 3 and Figure 2.

\subsection*{Diagnostic accuracy}

{\label{diagnostic-accuracy}}

The characteristics of women in the development and evaluation cohorts
were similar (see Table 1). Of the 50 women in the evaluation cohort, 15
(30\%) had chorioamnionitis and 35 (70\%) did not have any infection.
The median CRP values among women with and without infection were 30.0
mg/L and 8.1 mg/L, respectively (Mann-Whitney test
p\textsubscript{diff}\textless{}0.001).

The overall diagnostic accuracy of CRP for infection was significantly
higher when using a pregnancy-specific upper reference limit of 18 mg/L,
compared to 7 mg/L (p=0.002) (see Figure 3). The sensitivity and
specificity using the pregnancy-specific reference limit were 80\% and
86\%, respectively. Summary statistics on diagnostic accuracy for both
reference limits are presented in Table 4.

\section*{Discussion}

{\label{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,\textsuperscript{10} and [?]10 mg/L
in the US and Australia.\textsuperscript{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).\textsuperscript{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.\textsuperscript{21} Studies of other
blood biomarkers have reported better diagnostic accuracy when using
pregnancy-specific reference intervals: Girling, \emph{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.\textsuperscript{22}

Adipose tissue is known to mount an immune response to
overnutrition,\textsuperscript{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
pregnant\textsuperscript{24, 25} and non-pregnant
populations,\textsuperscript{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.

\subsection*{Strengths and weaknesses}

{\label{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.\textsuperscript{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 chorioamnionitis\textsuperscript{20}and
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.

\subsection*{Conclusions}

{\label{conclusions-1}}

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.

\section*{Disclosure of interests}

{\label{disclosure-of-interests}}

The authors declare no conflicts of interest.

\section*{Acknowledgements}

{\label{acknowledgements}}

We are grateful to Sarah Hutchinson for identifying and managing the
blood samples.

\section*{Contributions}

{\label{contributions}}

Study concept (SD, MV, TJ), data synthesis (JB), data extraction (SD,
MV), data analysis (SD, MV, TJ), manuscript preparation (SD, JB, TJ, BS,
LI, MV), guarantor (MV).

\section*{Ethics}

{\label{ethics}}

This study was undertaken within the recommendations of the pre-existing
ethics approval for the Oxford Pregnancy Biobank (REC 07/H0607/74).

\section*{Funding}

{\label{funding-1}}

Abbott Laboratories provided reagents and funding for this study, but
were not involved in the study design, data interpretation or writing of
this manuscript.

\section*{References}

{\label{references}}

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\section*{Table 1: Participant
characteristics.}

{\label{table-1-participant-characteristics.}}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Variable}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{All women}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Body mass index}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Body mass index}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Body mass index}\strut
\end{minipage} & \begin{minipage}[b]{0.16\columnwidth}\raggedright\strut
\textbf{Missing} \textbf{(n, \%)}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{\textless{}25 kg/m\textsuperscript{2}}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{[?]25 kg/m\textsuperscript{2}}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{P\textsubscript{diff}\textsuperscript{a}}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Development cohort}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
n\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
315\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
182 (57.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
133 (42.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Age, years\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
30.5 (5.1)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
30.3 (5.1)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
30.8 (5.1)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.41\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Body mass index (kg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
25.1 (4.3)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
22.2 (1.6)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
29.2 (3.5)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Mean arterial pressure (mmHg)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
79.3 (7.9)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
77.1 (7.5)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
82.1 (7.4)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{\textless{}0.0001}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5 (1.6\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
White ethnicity (n, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
293 (93.0\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
166 (91.2\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
127 (95.5\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.15\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
4 (1.3\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Gestation at delivery (weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
40.4 (1.2)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
40.3 (1.2)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
40.5 (1.1)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.24\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Neonatal birthweight (kg)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3.5 (0.5)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3.4 (0.5)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
3.6 (0.5)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{\textless{}0.001}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Neonatal admission (n, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
6 (1.9\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
5 (2.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
1 (0.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.91\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Fetal sex, male (n, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
164 (52.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
96 (52.8\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
68 (51.1\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
0.84\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\textbf{Evaluation cohort}\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
n\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
50\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Cases (n, \%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
15 (30\%)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Age, years\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
32.0 (5.2)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Body mass index (kg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
27.2 (5.6)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
Gestation at amniocentesis (weeks)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
22.9 (3.4)\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.14\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Values shown are means with standard deviations, or frequencies with
proportions. Data on age, body mass index and mean arterial pressure
were taken at recruitment.

\textsuperscript{a}Student's t-test or Chi\textsuperscript{2} between
groups.

\section*{Table 2: Reference intervals for
CRP.}

{\label{table-2-reference-intervals-for-crp.}}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Calculated reference interval} \textbf{(mg/L)}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Calculated reference interval} \textbf{(mg/L)}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Suggested reference interval} \textbf{(mg/L)}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Trimester}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Upper limit} \textbf{(90\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{Lower limit} \textbf{(90\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
First\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
21.48 (18.64-24.74)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.46 (0.38-0.57)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textless{}18\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Second\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
20.46 (17.91-23.38)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.73 (0.63-0.84)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Third\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
18.90 (16.45-21.73)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.75 (0.67-0.83)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\section*{Table 3: Partitioned reference intervals for CRP by body mass
index}

{\label{table-3-partitioned-reference-intervals-for-crp-by-body-mass-index}}\selectlanguage{english}
\begin{longtable}[]{@{}llllllllll@{}}
\toprule
\begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Trimester}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Body mass} \textbf{index}
\textbf{(kg/m\textsuperscript{2})}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Reference interval (mg/L)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Reference interval (mg/L)}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{R}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{D\textsubscript{U}}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{D\textsubscript{L}}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Justification for partitioning}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Justification for partitioning}\strut
\end{minipage} & \begin{minipage}[b]{0.10\columnwidth}\raggedright\strut
\textbf{Justification for partitioning}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Upper limit} \textbf{(90\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Lower limit} \textbf{(90\% CI)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{R criteria}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{D\textsubscript{U} criteria}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{D\textsubscript{L} criteria}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
First\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textless{}25\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
14.73 (12.32-17.61)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.33 (0.25-0.44)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.09\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.73\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{1.07}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Not met\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Marginal\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Met}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
[?]25\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
26.01 (21.48-31.49)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.04 (0.82-1.30)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Second\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textless{}25\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
13.41 (11.43-15.74)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.63 (0.53-0.75)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.98\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{0.91}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{0.81}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Not met\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Met}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Met}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
[?]25\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
27.00 (22.28-32.73)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.20 (0.99-1.47)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Third\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textless{}25\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
13.88 (11.66-16.52)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.67 (0.59-0.77)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.01\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.65\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.63\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Not met\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Marginal\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Marginal\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
[?]25\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
24.03 (19.55-29.55)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.02 (0.86-1.21)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

R is the ratio of standard deviations for groups of body mass index.
D\textsubscript{U/L} is the absolute difference in upper or lower
reference limits between groups of body mass index, divided by the
smaller of the two standard deviations. Partitioning is justified
statistically where R\textgreater{}1.5, or D\textsubscript{U/L} is
[?]0.75. Partitioning may be considered where D\textsubscript{U/L} is
[?]0.25 but \textless{}0.75. A common reference interval for CRP should be
used where D\textsubscript{U/L} is \textless{}0.25.\textsuperscript{17}

\section*{Table 4: Diagnostic accuracy of CRP for
chorioamnionitis}

{\label{table-4-diagnostic-accuracy-of-crp-for-chorioamnionitis}}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Reference} \textbf{interval}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{n}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Cases}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Sensitivity}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{Specificity}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{PPV}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{NPV}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{AUC\textsuperscript{a}}\strut
\end{minipage} & \begin{minipage}[b]{0.11\columnwidth}\raggedright\strut
\textbf{P\textsubscript{diff}\textsuperscript{b}}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
[?]7 mg/L\textsuperscript{c}\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
50\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
87\%\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
46\%\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
41\%\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
89\%\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.66\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textbf{0.002}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\textless{}18 mg/L\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
80\%\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
86\%\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
71\%\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
91\%\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
0.83\strut
\end{minipage} & \begin{minipage}[t]{0.08\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: PPV (positive predictive value), NPV (negative predictive
value).

\textsuperscript{a}Area under the receiving operator
curve.\textsuperscript{b}Non-parametric receiving operator curve
analysis.\textsuperscript{c}Derived from Royal College of Obstetricians
and Gynaecologists guidance on bacterial sepsis in
pregnancy.\textsuperscript{10}

\section*{Figure 1: CRP by body mass index (third
trimester)}

{\label{figure-1-crp-by-body-mass-index-third-trimester}}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Caption: Adjusted for maternal age, mean arterial pressure and
ethnicity.

\section*{Figure 2: Upper reference limits for CRP with 90\% confidence
intervals}

{\label{figure-2-upper-reference-limits-for-crp-with-90-confidence-intervals}}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\section*{Figure 3: Areas under the receiving operator
curves}

{\label{figure-3-areas-under-the-receiving-operator-curves}}

\selectlanguage{english}
\FloatBarrier
\end{document}

