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OBSTETRICS
C-reactive protein levels in early pregnancy, fetal
growth patterns, and the risk for neonatal
complications: the Generation R Study
Gesina D. S. Ernst, MSc; Layla L. de Jonge, MD; Albert Hofman, MD, PhD; Jan Lindemans, PhD;
Henk Russcher, PhD; Eric A. P. Steegers, MD, PhD; Vincent W. V. Jaddoe, MD, PhD

OBJECTIVE: We sought to examine the associations of maternal C-re- ⫺29 g, 95% confidence interval [CI], ⫺58 to 0 and ⫺128 g, 95% CI,
active protein (CRP) levels with fetal growth and the risks of neonatal ⫺195 to ⫺60, respectively). Elevated maternal CRP levels were also asso-
complications. ciated with an increased risk of a small size for gestational age in the off-
spring (adjusted odds ratio, 2.94; 95% CI, 1.61–5.36).
STUDY DESIGN: CRP levels were measured in early pregnancy in 6016
women. Main outcome measures were fetal growth in each trimester CONCLUSION: Maternal CRP levels in early pregnancy are associ-
and neonatal complications. ated with fetal growth restriction and increased risks of neonatal
complications.
RESULTS: As compared to the reference group (CRP levels ⬍5 mg/L), el-
evated maternal CRP levels (ⱖ25 mg/L) were associated with lower esti- Key words: cohort studies, C-reactive protein, fetal growth,
mated fetal weight in third trimester and lower weight at birth (differences: inflammation, neonatal complications, pregnancy

Cite this article as: Ernst GDS, de Jonge LL, Hofman A, et al. C-reactive protein levels in early pregnancy, fetal growth patterns, and the risk for neonatal
complications: the Generation R Study. Am J Obstet Gynecol 2011;205:132.e1-8.

C -reactive protein (CRP) is an acute-


phase reactant and a frequently
used marker of low-grade systemic in-
tious exposures.1 Elevated CRP levels are
associated with increased risks of com-
mon diseases such as cardiovascular dis-
reflect causal pathways.4,5 Elevated CRP
levels during pregnancy, as a marker of
low-grade inflammation, have also been
flammation. Its levels increase in re- ease and type 2 diabetes.2,3 However, it is suggested to be associated with increased
sponse to both infectious and noninfec- still not clear whether these associations risks of fetal growth restriction and neo-
natal complications, such as preterm
birth, low birthweight, and small size for
From the Generation R Study Group (Ms Ernst and Drs de Jonge and Jaddoe) and the gestational age (SGA).6-8 Low-grade in-
Departments of Pediatrics (Ms Ernst and Drs de Jonge and Jaddoe), Epidemiology (Ms Ernst flammation is associated with endothe-
and Drs de Jonge, Hofman, and Jaddoe), Clinical Chemistry (Drs Lindemans and Russcher), lial dysfunction, leading to vascular
and Obstetrics and Gynaecology (Dr Steegers), Erasmus Medical Center, Rotterdam, The dysfunction and suboptimal placental
Netherlands.
development. Maternal systemic inflam-
Presented as a poster at the 34th Annual Conference of Werkgroep Epidemiologisch Onderzoek
mation might also be a response to isch-
Nederland, Nijmegen, The Netherlands, June 10-11, 2010, and as a poster at the Fifth
Conference of Epidemiological Longitudinal Studies in Europe, Paphos, Cyprus, Oct. 13-15, emia of the placenta, due to suboptimal
2010. placentation.9,10 Subsequently, subopti-
Received Nov. 22, 2010; revised Feb. 23, 2011; accepted March 29, 2011. mal placental development might pre-
Reprints: Vincent W. V. Jaddoe, MD, PhD, the Generation R Study Group (AE-006), Erasmus dispose mothers to increased risks for
Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands. v.jaddoe@erasmusmc.nl. various pregnancy complications.11,12
The first 2 authors contributed equally to this article. Although the association of elevated
The Generation R Study is conducted by the Erasmus Medical Center in close collaboration with CRP levels with preterm birth has been
the School of Law and the Faculty of Social Sciences at the Erasmus University, Rotterdam; the shown in several studies, results from
Municipal Health Service, Rotterdam area; and the Stichting Trombosedienst and
Artsenlaboratorium Rijnmond (Star-MDC), Rotterdam.
studies relating CRP levels with fetal
The general design of the Generation R Study was made possible by financial support from the
growth measures or neonatal complica-
Erasmus Medical Center, Rotterdam; Erasmus University, Rotterdam; the Dutch Ministry of tions are not consistent.7,8,13,14 Differ-
Health, Welfare and Sport; and The Netherlands Organization for Health Research and ences in results might be due to differ-
Development (ZonMw). Further support for the present study was obtained from the Dutch Heart ences in study designs and populations. It
Foundation (2008B114) and Abbott Diagnostics B.V., Hoofddorp, The Netherlands. Dr Jaddoe
is not known whether and in which trimes-
received additional grants from The Netherlands Organization for Health Research and
Development (ZonMw 90700303, 916.10159). ter CRP levels affect fetal growth measures.
0002-9378/$36.00 • © 2011 Mosby, Inc. All rights reserved. • doi: 10.1016/j.ajog.2011.03.049 In a population-based prospective
cohort study among 6016 pregnant

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women, we examined the associations of was 1.3% at 12.9 mg/L and 1.2% at 39.9 shoes and heavy clothing and body mass
maternal CRP levels, as marker of low- mg/L. The lowest level of detection was 0.2 index (BMI) was calculated (weight/
grade inflammation in early pregnancy, mg/L. We created 6 categories of CRP lev- height2 [kg/m2]) at enrollment.21 Mater-
with fetal growth characteristics in dif- els (⬍5.0, 5.0-9.9, 10.0-14.9, 15.0-19.9, nal systolic and diastolic blood pressure
ferent trimesters of pregnancy and the 20.0-24.9, and ⱖ25 mg/L). Levels ⬍5.0 were measured at intake, using standard-
risks of neonatal complications. mg/L and ⱖ25 mg/L were considered ized methods. For each participant, the
as low (reference) and elevated levels, mean value of 2 blood pressure readings
M ATERIALS AND M ETHODS respectively. over a 60-second interval was docu-
Design and population mented.22 Folate levels were analyzed
This study was embedded in the Gener- Fetal growth characteristics from venous samples drawn in the first
ation R Study, a population-based pro- Fetal ultrasound examinations were trimester of pregnancy. Maternal age
spective cohort study from early fetal life performed in 1 of the 2 dedicated re- was registered at enrollment.
onward in the city of Rotterdam, The search centers in each trimester of
Netherlands.15 Enrollment was aimed in pregnancy. Median gestational age for Statistical analysis
early pregnancy but was allowed until first, second, and third trimester visits We assessed the associations of maternal
birth of the child. All mothers were en- were 12.4 weeks (95% range, 10.7–14.5), characteristics with CRP levels as out-
rolled from 2001 through 2005. Re- 20.5 weeks (95% range, 18.7–23.1), and come levels using multivariate linear re-
sponse rate was 61%.15 The study was 30.4 weeks (95% range, 28.6 –32.8), re- gression models. Since CRP levels were
approved by the Medical Ethical Com- spectively. In the second and third tri- not normally distributed, we applied a
mittee of the Erasmus MC, Rotterdam. mester of pregnancy, we measured fetal logarithmic transformation for these
Written informed consent was obtained head circumference, abdominal circum- analyses. Results are presented as geo-
from all participants. ference, and femur length to the nearest metric means (95% range) per determi-
Of the total of 8880 mothers who were millimeter using standardized ultra- nant category and an overall P for trend
enrolled during pregnancy, 76% (n ⫽ sound procedures.18 Estimated fetal based on these regression models. Asso-
6748) were enrolled before a gestational weight was calculated using the formula ciations of CRP levels with fetal growth
age of 18 weeks.15 Of these mothers, by Hadlock et al.19 Longitudinal growth characteristics were assessed using linear
blood plasma samples were collected in curves and gestational age-adjusted SD regression models. These models were
95% (n ⫽ 6398) and CRP was success- scores (SDS) were constructed for all fe- adjusted for gestational age at the mea-
fully measured in 90% (n ⫽ 6091). tal growth measurements.20 surement, fetal sex, and maternal age,
Mothers with extremely high CRP levels Information about offspring sex, ges- BMI, education, ethnicity, parity, smok-
(⬎100 mg/L) (n ⫽ 6), and mothers with tational age, weight, length, and head cir- ing, alcohol consumption. BMI is known
twin pregnancies (n ⫽ 69) were ex- cumference at birth was obtained from to be highly correlated with levels of
cluded, leaving 6016 mothers with sin- medical records and registries. Since CRP,23 and with birthweight,21,24 and
gleton live births for analysis (Supple- head circumference and length at birth therefore expected to be our main con-
mentary Figure S1). were not routinely measured at birth, founder. Further variables were included
missing birth measures were completed in these models based on their associa-
High-sensitivity CRP levels with data from the first-month visit at tion with both the CRP levels and preg-
Maternal venous blood samples were the routine child health center. Preterm nancy outcomes, or a 10% change in the
collected in early pregnancy (median, birth was defined as a gestational age of effect estimate. Next, we assessed the as-
13.2; 95% range, 9.6 –17.6 weeks) and ⬍37 weeks at delivery, low birthweight sociations of CRP level with the risks of
transported to the regional laboratory was defined as birthweight ⬍2500 g, and neonatal complications (preterm birth,
(Star-MDC, Rotterdam, The Netherlands) SGA at birth was defined as a sex-specific low birthweight, and SGA). These mod-
for processing and storage.16 Blood sam- gestational age-adjusted birthweight be- els were adjusted for maternal age, BMI,
ples were stored at ⫺80°C. CRP concen- low the fifth percentile in the study co- education, ethnicity, parity, smoking, al-
trations were measured in EDTA plasma hort (SDS ⱕ1.81 for boys and ⱕ1.78 for cohol consumption and folic acid level at
samples at the Department of Clinical girls). intake. Tests for trends were performed
Chemistry of the Erasmus MC in 2009. We using CRP as continuous variable in
measured high-sensitivity CRP since tradi- Covariates multivariate linear and logistic regres-
tional clinically used CRP methods lack the Information about maternal educational sion analyses. The percentages of miss-
sensitivity in low ranges needed for pre- level, ethnicity and parity was obtained ing values within the population for
dicting future risk of events in apparently by a questionnaire at enrollment in the analysis were ⬍1% for continuous data
healthy individuals.17 CRP levels were study. Maternal smoking and alcohol and ⬍13% for the categorical data. We
analyzed using an immunoturbidimetric consumption habits were assessed by applied multiple imputation for covari-
assay on the Architect System (Abbot questionnaires in each trimester. Mater- ates.25 Since there were no major differ-
Diagnostics B.V., Hoofddorp, The Nether- nal anthropometrics, including height ences in the observed results between
lands). The within run precision for CRP and weight, were measured without analyses with imputed missing data or

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Research Obstetrics www.AJOG.org

complete cases only, only results includ-


ing imputed missing data are presented. TABLE 1
All measures of association are presented Characteristics of study participants
with their 95% confidence intervals Maternal characteristics at enrollment (n ⴝ 6016) n
(CIs). All statistical analyses were per- Age, y 29.8 ⫾ 5.1
..............................................................................................................................................................................................................................................
formed using the SPSS, version 17.0 for Height, cm 167.6 ⫾ 7.4
Windows (SPSS Inc, Chicago, IL). ..............................................................................................................................................................................................................................................
Weight, kg 68.8 ⫾ 13.1
..............................................................................................................................................................................................................................................
Body mass index, kg/m 2
24.5 ⫾ 4.4
..............................................................................................................................................................................................................................................
R ESULTS Parity
.....................................................................................................................................................................................................................................
Maternal age ranged from 15.3– 46.3 0 3412 (56.7)
.....................................................................................................................................................................................................................................
years, with a mean of 29.8 years (Table
1 1797 (29.9)
1). Median CRP level was 4.5 mg/L (95% .....................................................................................................................................................................................................................................

range, 0.60 –25.46). Mean offspring ⱖ2 756 (12.6)


.....................................................................................................................................................................................................................................
birthweight was 3420 g (SD 564), and Missing 51 (0.8)
..............................................................................................................................................................................................................................................
median gestational age at birth was 40.1 Highest completed educational level
.....................................................................................................................................................................................................................................
weeks (95% range, 35.6 – 42.3). Maternal Primary school 549 (9.1)
education, BMI, parity, and gestational .....................................................................................................................................................................................................................................

age were associated with CRP levels. Secondary school 2534 (42.1)
.....................................................................................................................................................................................................................................

Mothers with a higher parity had a Higher education 2505 (41.6)


.....................................................................................................................................................................................................................................
higher mean CRP level (means for CRP Missing 428 (7.1)
..............................................................................................................................................................................................................................................
levels from 3.84 mg/L for a parity of Ethnic background
0-6.15 mg/L with a parity of ⱖ2) and .....................................................................................................................................................................................................................................
European 3502 (58.2)
lower maternal education was associated .....................................................................................................................................................................................................................................

with higher CRP levels (means for CRP Non-European 2171 (36.1)
.....................................................................................................................................................................................................................................
levels from 5.40 mg/L for mothers with Missing 343 (5.7)
..............................................................................................................................................................................................................................................
primary school only to 3.62 mg/L for Smoking during pregnancy
.....................................................................................................................................................................................................................................
mothers with higher education). A
Not 3865 (64.2)
strong effect was seen for maternal BMI, .....................................................................................................................................................................................................................................

with monotonous increasing means for First trimester only 480 (8.0)
.....................................................................................................................................................................................................................................

CRP from 2.78 mg/L for the group with Continued 908 (15.1)
.....................................................................................................................................................................................................................................
BMI ⬍20 to 10.87 mg/L for the group Missing 763 (12.7)
with BMI ⱖ35 (Supplementary Table S1
..............................................................................................................................................................................................................................................
Alcohol consumption during pregnancy
and Supplementary Figure S2). .....................................................................................................................................................................................................................................
Not 2424 (40.3)
As compared to maternal CRP levels .....................................................................................................................................................................................................................................

of ⬍5.0 mg/L, maternal CRP levels of First trimester only 792 (13.2)
.....................................................................................................................................................................................................................................
ⱖ25 mg/L were inversely associated with Continued 2065 (34.3)
.....................................................................................................................................................................................................................................
estimated fetal weight in third trimester Missing 735 (12.2)
and with birthweight (difference ⫺29 g, ..............................................................................................................................................................................................................................................
Gestational age at enrollment 13.2 (9.6–17.6)
95% CI, ⫺58 to 0 and ⫺128 g, 95% CI, ..............................................................................................................................................................................................................................................

⫺195 to ⫺60, respectively). No consis- C-reactive protein level, mg/L 4.5 (0.60–25.46)
..............................................................................................................................................................................................................................................
tent associations were observed between Folic acid level, nmol/L 15.70 (5.50–37.50)
..............................................................................................................................................................................................................................................
maternal CRP levels in early pregnancy Birth characteristics
.....................................................................................................................................................................................................................................
and fetal head circumference in second
Birthweight, g 3420 ⫾ 564
or third trimester or at birth (Table 2). .....................................................................................................................................................................................................................................

We used femur length in second and Gestational age at birth, wk (median) 40.1 (35.6–42.3)
.....................................................................................................................................................................................................................................

third trimester and body length at birth Males 3032 (50.4)


.....................................................................................................................................................................................................................................
as fetal length measures. Maternal CRP Preterm birth, ⬍37 wk 302 (5.0)
.....................................................................................................................................................................................................................................
levels were not consistently associated Low birthweight, ⬍2500 g 293 (4.9)
with fetal length. The Figure shows that, .....................................................................................................................................................................................................................................
Small size for gestational age, ⱕ5th percentile 299 (5.0)
as compared to levels of ⬍5.0 mg/L, the ..............................................................................................................................................................................................................................................

relative effect of CRP levels of ⱖ25.0 Values are presented as means (SD) or number (%).
Gestational age at enrollment and at birth and C-reactive protein level and folic acid level values are presented as median (95% range).
mg/L on fetal head circumference, Ernst. C-reactive protein levels in pregnancy and fetal growth. Am J Obstet Gynecol 2011.
length, and weight, presented as differ-
ence in SDS, tended to be greater at birth.

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TABLE 2
C-reactive protein levels and fetal growth
Second trimester Third trimester Birth
Head circumference
Head circumference (n ⴝ 5774) Head circumference (n ⴝ 5748) Head circumference (n ⴝ 4743)
C-reactive
protein No. of Difference, mm No. of Difference, mm No. of Difference, mm
level, mg/L children (95% CI) children (95% CI) children (95% CI)
⬍5.0 n ⫽ 3162 Reference n ⫽ 3153 Reference n ⫽ 2638 Reference
................................................................................................................................................................................................................................................................................................................................................................................
5.0-9.9 n ⫽ 1573 ⫺0.07 (⫺0.44 to 0.31) n ⫽ 1566 0.10 (⫺0.45 to 0.66) n ⫽ 1300 ⫺0.08 (⫺1.05 to 0.88)
................................................................................................................................................................................................................................................................................................................................................................................
10.0-14.9 n ⫽ 570 ⫺0.21 (⫺0.77 to 0.35) n ⫽ 563 ⫺0.34 (⫺1.17 to 0.48) n ⫽ 437 ⫺1.85 (⫺3.33 to ⫺0.36)
................................................................................................................................................................................................................................................................................................................................................................................
15.0-19.9 n ⫽ 210 ⫺0.37 (⫺1.24 to 0.50) n ⫽ 206 0.07 (⫺1.22 to 1.36) n ⫽ 162 ⫺0.50 (⫺2.80 to 1.81)
................................................................................................................................................................................................................................................................................................................................................................................
20.0-24.9 n ⫽ 109 0.44 (⫺0.73 to 1.61) n ⫽ 107 ⫺1.21 (⫺2.95 to 0.54) n ⫽ 82 ⫺1.02 (⫺4.18 to ⫺2.14)
................................................................................................................................................................................................................................................................................................................................................................................
ⱖ25.0 n ⫽ 150 ⫺0.75 (⫺1.76 to 0.25) n ⫽ 153 ⫺0.51 (⫺1.99 to 0.96) n ⫽ 124 ⫺1.49 (⫺4.08 to 1.10)
................................................................................................................................................................................................................................................................................................................................................................................
P for trend .240 .300 .109
Length
Femur length (n ⴝ 5787) Femur length (n ⴝ 5789) Birth length (n ⴝ 4804)
C-reactive
protein No. of Difference, mm No. of Difference, mm No. of Difference, mm
level, mg/L children (95% CI) children (95% CI) children (95% CI)
⬍5.0 n ⫽ 3174 Reference n ⫽ 3176 Reference n ⫽ 2659 Reference
................................................................................................................................................................................................................................................................................................................................................................................
5.0-9.9 n ⫽ 1569 0.10 (⫺0.01 to 0.21) n ⫽ 1578 0.03 (⫺0.10 to 0.17) n ⫽ 1313 ⫺0.01 (⫺1.38 to 1.37)
................................................................................................................................................................................................................................................................................................................................................................................
10.0-14.9 n ⫽ 575 0.08 (⫺0.08 to 0.24) n ⫽ 565 0.04 (⫺0.16 to 0.24) n ⫽ 458 ⫺1.00 (⫺3.08 to 1.08)
................................................................................................................................................................................................................................................................................................................................................................................
15.0-19.9 n ⫽ 210 0.03 (⫺0.22 to 0.28) n ⫽ 208 0.06 (⫺0.25 to 0.37) n ⫽ 168 ⫺0.23 (⫺3.46 to 3.01)
................................................................................................................................................................................................................................................................................................................................................................................
20.0-24.9 n ⫽ 109 0.22 (⫺0.12 to 0.56) n ⫽ 108 0.18 (⫺0.25 to 0.37) n ⫽ 80 ⫺3.08 (⫺7.63 to 1.46)
................................................................................................................................................................................................................................................................................................................................................................................
ⱖ25.0 n ⫽ 150 ⫺0.18 (⫺0.47 to 0.11) n ⫽ 154 ⫺0.27 (⫺0.63 to 0.09) n ⫽ 126 ⫺2.74 (⫺6.40 to 0.92)
................................................................................................................................................................................................................................................................................................................................................................................
P for trend .972 .395 .275
Weight
Estimated fetal weight Estimated fetal weight Birthweight
(n ⴝ 5763) (n ⴝ 5768) (n ⴝ 5979)
C-reactive
protein No. of Difference, g No. of Difference, g No. of Difference, g
level, mg/L children (95% CI) children (95% CI) children (95% CI)
⬍5.0 n ⫽ 3161 Reference n ⫽ 3167 Reference n ⫽ 3271 Reference
................................................................................................................................................................................................................................................................................................................................................................................
5.0-9.9 n ⫽ 1559 ⫺1 (⫺3 to 2) n ⫽ 1570 7 (⫺4 to 18) n ⫽ 1630 10 (⫺15 to 36)
................................................................................................................................................................................................................................................................................................................................................................................
10.0-14.9 n ⫽ 575 1 (⫺3 to 4) n ⫽ 562 ⫺3 (⫺20 to 13) n ⫽ 586 ⫺47 (⫺85 to ⫺9)
................................................................................................................................................................................................................................................................................................................................................................................
15.0-19.9 n ⫽ 209 0 (⫺6 to 6) n ⫽ 207 14 (⫺12 to 46) n ⫽ 221 ⫺28 (⫺87 to 30)
................................................................................................................................................................................................................................................................................................................................................................................
20.0-24.9 n ⫽ 109 3 (⫺5 to 10) n ⫽ 108 12 (⫺23 to 46) n ⫽ 112 ⫺86 (⫺165 to ⫺6)
................................................................................................................................................................................................................................................................................................................................................................................
ⱖ25.0 n ⫽ 150 ⫺6 (⫺12 to 1) n ⫽ 154 ⫺29 (⫺58 to 0) n ⫽ 159 ⫺128 (⫺195 to ⫺60)
................................................................................................................................................................................................................................................................................................................................................................................
P for trend .274 .115 ⬍ .001
................................................................................................................................................................................................................................................................................................................................................................................
All models were adjusted for maternal age, body mass index, height, systolic and diastolic blood pressure at intake, education, ethnicity, parity, smoking, alcohol, folic acid level at intake, gestational
age at measurement, gestational age at blood collection, and fetal sex.
CI, confidence interval.
Ernst. C-reactive protein levels in pregnancy and fetal growth. Am J Obstet Gynecol 2011.

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Table 3 presents both the unadjusted


FIGURE
and adjusted associations of CRP levels
Elevated maternal C-reactive protein levels
with the risks of neonatal complications.
and fetal growth characteristics
The differences between the unadjusted
and adjusted models were mainly ex-
plained by including maternal BMI in
the models. The adjusted models show
that as compared to the reference cate-
gory (CRP levels ⬍5.0 mg/L) mothers
with elevated CRP levels (ⱖ25.0 mg/L)
were more likely to deliver children with
a SGA at birth (adjusted odds ratio, 2.94;
95% CI, 1.61–5.36). Mothers with ele-
vated CRP levels (ⱖ25.0 mg/L) tended to
be more likely to deliver preterm (ad-
justed odds ratio, 1.42; 95% CI, 0.69 –
2.89) or a child with a low birthweight
(adjusted odds ratio, 1.43; 95% CI, 0.67–
3.03), as compared to the reference cate-
gory, although not significantly.

C OMMENT
In this population-based prospective co-
hort study, we observed associations of
maternal sociodemographic and anthro-
pometric measures and lifestyle habits
with CRP levels in early pregnancy. After
adjustment for these variables, elevated
maternal CRP levels (ⱖ25.0 mg/L) in
early pregnancy were associated with fe-
tal growth restriction, and increased
risks of preterm birth and SGA at birth.
CRP is known to be slightly elevated
during pregnancy, due to the maternal
inflammatory reaction to the preg-
nancy.26 Previous studies showed that
measures of unhealthy lifestyle habits
such as cigarette smoking are also asso-
ciated with elevated CRP levels, whereas
moderate alcohol consumption and in-
creased physical activity are associated
with lower CRP levels.27-29 Increased Values are regression coefficients (95% confidence interval) and represent the difference in growth
BMI and adiposity are strongly associ- SDS between elevated levels of maternal C-reactive protein levels in early pregnancy (ⱖ25 mg/L) as
ated with elevated CRP levels.30,31 In our compared to the reference group (⬍5.0 mg/L). All models were adjusted for maternal age, body mass
population-based cohort among preg- index, height, systolic and diastolic blood pressure at intake, education, ethnicity, parity, smoking,
nant women, maternal BMI, parity, and alcohol, folic acid level at intake, gestational age at blood collection and fetal sex.
smoking during pregnancy were all SDS, standard deviation score.
positively associated with CRP levels. Ernst. C-reactive protein levels in pregnancy and fetal growth. Am J Obstet Gynecol 2011.

Higher maternal education, European


background, and continued maternal al- Our results indicate that elevated CRP important from an etiological perspec-
cohol consumption were associated with levels, as a marker of maternal low-grade tive or on population level. Future stud-
lower CRP levels. Our results suggest inflammation, are associated with fetal ies should explore the role of CRP levels
that markers of unhealthy lifestyle habits growth restriction. The effect estimates in clinical practice.
lead to elevated CRP levels. are relatively small. Our findings may be We did observe an association be-

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TABLE 3
C-reactive protein levels and neonatal complications
Preterm birth, <37 wk of gestation
C-reactive protein No. of No. of Odds ratio Adjusted odds ratio
level, mg/L children cases (95% CI) P value (95% CI) P value
⬍5.0 3284 141 1.00 1.00
................................................................................................................................................................................................................................................................................................................................................................................
5.0-9.9 1646 88 1.26 (0.96–1.65) .10 1.25 (0.94–1.66) .12
................................................................................................................................................................................................................................................................................................................................................................................
10.0-14.9 590 40 1.62 (1.27–2.32) .01 1.69 (1.15–2.47) .01
................................................................................................................................................................................................................................................................................................................................................................................
15.0-19.9 222 17 1.85 (1.09–3.11) .02 1.86 (1.07–3.23) .03
................................................................................................................................................................................................................................................................................................................................................................................
20.0-24.9 112 7 1.49 (0.68–3.24) .32 1.69 (0.64–3.23) .38
................................................................................................................................................................................................................................................................................................................................................................................
ⱖ25.0 159 9 1.34 (0.67–2.66) .42 1.42 (0.69–2.89) .34
................................................................................................................................................................................................................................................................................................................................................................................
P for trend .075 .109
Low birthweight, <2500 g
C-reactive protein No. of No. of Odds ratio Adjusted odds ratio
level, mg/L children cases (95% CI) P value (95% CI) P value
⬍5.0 3271 154 1.00 1.00
................................................................................................................................................................................................................................................................................................................................................................................
5.0-9.9 1630 84 1.09 (0.83–1.43) .54 1.18 (0.89–1.57) .25
................................................................................................................................................................................................................................................................................................................................................................................
10.0-14.9 586 31 1.12 (0.75–1.66) .59 1.40 (0.92–2.12) .12
................................................................................................................................................................................................................................................................................................................................................................................
15.0-19.9 221 11 1.05 (0.56–1.95) .89 1.35 (0.70–2.59) .38
................................................................................................................................................................................................................................................................................................................................................................................
20.0-24.9 112 5 0.94 (0.38–2.32) .89 1.11 (0.43–2.86) .82
................................................................................................................................................................................................................................................................................................................................................................................
ⱖ25.0 159 8 1.05 (0.51–2.17) .90 1.43 (0.67–3.03) .36
................................................................................................................................................................................................................................................................................................................................................................................
P for trend .990 .280
Small for gestational age, <5%
C-reactive protein No. of No. of Odds ratio Adjusted odds ratio
level, mg/L children cases (95% CI) P value (95% CI) P value
⬍5.0 3263 168 1.00 1.00
................................................................................................................................................................................................................................................................................................................................................................................
5.0-9.9 1629 73 0.86 (0.65–1.14) .30 0.98 (0.73–1.31) .88
................................................................................................................................................................................................................................................................................................................................................................................
10.0-14.9 585 29 0.96 (0.64–1.43) .82 1.32 (0.86–2.01) .21
................................................................................................................................................................................................................................................................................................................................................................................
15.0-19.9 221 10 0.87 (0.45–1.66) .67 1.31 (0.66–2.59) .44
................................................................................................................................................................................................................................................................................................................................................................................
20.0-24.9 112 5 0.86 (0.74–2.12) .74 1.23 (0.48–3.16) .66
................................................................................................................................................................................................................................................................................................................................................................................
ⱖ25.0 159 14 1.76 (1.00–3.11) .05 2.94 (1.61–5.36) ⬍ .01
................................................................................................................................................................................................................................................................................................................................................................................
P for trend .379 .003
................................................................................................................................................................................................................................................................................................................................................................................
Adjusted odds ratios were adjusted for maternal age, body mass index, height, systolic and diastolic blood pressure at intake, education, ethnicity, parity, smoking, alcohol, folic acid level at intake,
and gestational age at blood collection.
CI, confidence interval.
Ernst. C-reactive protein levels in pregnancy and fetal growth. Am J Obstet Gynecol 2011.

tween elevated maternal CRP levels in ing that these associations are indepen- by elevated CRP levels, results in subop-
early pregnancy and the risk of SGA, dent of maternal BMI. Our results are in timal placental development,9,10 and
which remained significant after adjust- line with previous smaller studies, which subsequently increase the risks of preg-
ment. The differences between the unad- suggested an increased risk of preterm de- nancy complications. However, higher
justed and adjusted models were mainly livery among mothers with elevated CRP levels of CRP may also be associated with
explained by including maternal BMI in in early or mid-pregnancy. However, these vascular dysfunction that leads in turn to
the model. Maternal BMI is positively studies did not demonstrate associations suboptimal placental development.9,10
associated with CRP levels32 and fetal with fetal growth retardation.7,14 Both fetal growth and pregnancy-in-
growth.21 After adjusting our models for The mechanisms underlying these as- duced hypertensive disorders might
maternal BMI, elevated CRP levels were sociations should further be explored, have at least part of their origin in sub-
still associated with fetal growth restric- but might include that maternal low- optimal early placenta development.33
tion and increased risks of SGA, suggest- grade systemic inflammation, indicated Also, the associations might not reflect

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causality, since elevated CRP levels can 2. Danesh J, Wheeler JG, Hirschfield GM, et al. 17. Roberts WL, Moulton L, Law TC, et al. Eval-
be markers of other risk factors or pro- C-reactive protein and other circulating markers uation of nine automated high-sensitivity C-re-
of inflammation in the prediction of coronary active protein methods: implications for clinical
cesses leading fetal growth restriction. heart disease. N Engl J Med 2004;350: and epidemiological applications; part 2. Clin
Previous studies focused on the associa- 1387-97. Chem 2001;47:418-25.
tions of CRP genotypes and levels with 3. Emerging Risk Factors Collaboration; Kap- 18. Royal College of Obstetricians and Gynae-
cardiovascular disease, which used a toge S, Di Angelantonio E, Lowe G, et al. C-re- cologists. Routine ultrasound screening in
active protein concentration and risk of coro- pregnancy: protocol. London: RCOG Press;
mendelian randomization approach,
nary heart disease, stroke, and mortality: an 2000.
suggested that CRP is not causally related individual participant meta-analysis. Lancet 19. Hadlock FP, Harrist RB, Sharman RS, Deter
to cardiovascular disease but rather a 2010;375:132-40. RL, Park SK. Estimation of fetal weight with the
marker of other risk factors.4,5,34 Such 4. Zacho J, Tybjaerg-Hansen A, Jensen JS, use of head, body, and femur measurements–a
studies have not yet been performed in Grande P, Sillesen H, Nordestgaard BG. Genet- prospective study. Am J Obstet Gynecol
ically elevated C-reactive protein and ischemic 1985;151:333-7.
pregnancy.
vascular disease. N Engl J Med 2008;359: 20. Verburg BO, Steegers EA, De Ridder M, et
Some methodological issues need to 1897-908. al. New charts for ultrasound dating of preg-
be considered. To our knowledge, this is 5. Lawlor DA, Harbord RM, Timpson NJ, et al. nancy and assessment of fetal growth: longitu-
the largest cohort study that has exam- The association of C-reactive protein and CRP dinal data from a population-based cohort
ined the associations of maternal CRP genotype with coronary heart disease: findings study. Ultrasound Obstet Gynecol 2008;31:
from five studies with 4,610 cases amongst 388-96.
levels in early pregnancy and placenta re- 18,637 participants. PLoS One 2008;3:e3011. 21. Ay L, Kruithof CJ, Bakker R, et al. Maternal
lated complications in mother and child. 6. Grgic G, Skokic F, Bogdanovic G. C-reactive anthropometrics are associated with fetal size in
Of all mothers enrolled in pregnancy, protein as a biochemical marker of idiopathic different periods of pregnancy and at birth: the
76% enrolled in early pregnancy. Nonre- preterm delivery. Med Arh 2010;64:132-4. Generation R Study. BJOG 2009;116:953-63.
7. Pitiphat W, Gillman MW, Joshipura KJ, Wil-
sponse at baseline would lead to selec- 22. Bakker R, Steegers EA, Mackenbach JP,
liams PL, Douglass CW, Rich-Edwards JW.
tion bias if the associations would differ Hofman A, Jaddoe VW. Maternal smoking and
Plasma C-reactive protein in early pregnancy
blood pressure in different trimesters of preg-
between those with and without com- and preterm delivery. Am J Epidemiol 2005;
nancy: the Generation R Study. J Hypertens
plete data. This seems unlikely. Biased 162:1108-13.
2010;28:2210-8.
estimates in large cohort studies primar- 8. Tjoa ML, van Vugt JM, Go AT, Blankenstein
23. Qiu C, Sorensen TK, Luthy DA, Williams
MA, Oudejans CB, van Wijk IJ. Elevated C-re-
ily arise from loss to follow-up rather MA. A prospective study of maternal serum C-
active protein levels during first trimester of
than from nonresponse at baseline.35 pregnancy are indicative of preeclampsia and
reactive protein (CRP) concentrations and risk
Since follow-up information at birth was of gestational diabetes mellitus. Paediatr Peri-
intrauterine growth restriction. J Reprod Immu-
nat Epidemiol 2004;18:377-84.
available in 93%, we do not expect biased nol 2003;59:29-37.
24. Lowe LP, Metzger BE, Lowe WL Jr, Dyer
results due to loss to follow-up. We were 9. Lam C, Lim KH, Karumanchi SA. Circulating
AR, McDade TW, McIntyre HD. Inflammatory
angiogenic factors in the pathogenesis and pre-
able to adjust models for multiple poten- diction of preeclampsia. Hypertension 2005;
mediators and glucose in pregnancy: results
tial confounders, related to maternal so- from a subset of the hyperglycemia and adverse
46:1077-85.
ciodemographic status, anthropomet- 10. Redman CW, Sargent IL. Preeclampsia and pregnancy outcome (HAPO) study. J Clin En-
the systemic inflammatory response. Semin docrinol Metab 2010;95:5427-34.
rics, and lifestyle habits. However, as in 25. van Buuren S. Multiple imputation of dis-
all observational studies, residual con- Nephrol 2004;24:565-70.
11. Redman CW, Sargent IL. Placental stress crete and continuous data by fully conditional
founding due to unmeasured covariates and pre-eclampsia: a revised view. Placenta specification. Stat Methods Med Res 2007;16:
might still be the case. 2009;30(Suppl):S38-42. 219-42.
In conclusion, maternal low-grade in- 12. Roberts CT. IFPA Award in Placentology 26. von Versen-Hoeynck FM, Hubel CA, Galla-
Lecture: complicated interactions between her MJ, Gammill HS, Powers RW. Plasma levels
flammation in early pregnancy, as mea- of inflammatory markers neopterin, sialic acid,
genes and the environment in placentation,
sured by CRP levels, was associated with and C-reactive protein in pregnancy and pre-
pregnancy outcome and long term health. Pla-
fetal growth restriction and increased centa 2010;31(Suppl):S47-53. eclampsia. Am J Hypertens 2009;22:687-92.
risks of neonatal complications. Further 13. Bodnar LM, Ness RB, Harger GF, Roberts 27. Pirkola J, Vaarasmaki M, Ala-Korpela M, et
studies are needed to explore the under- JM. Inflammation and triglycerides partially me- al. Low-grade, systemic inflammation in adoles-
diate the effect of prepregnancy body mass in- cents: association with early-life factors, gen-
lying mechanisms and causality for these
dex on the risk of preeclampsia. Am J Epidemiol der, and lifestyle. Am J Epidemiol 2010;171:
associations. f
2005;162:1198-206. 72-82.
14. Lohsoonthorn V, Qiu C, Williams MA. Ma- 28. Oliveira A, Rodriguez-Artalejo F, Lopes C.
ternal serum C-reactive protein concentrations Alcohol intake and systemic markers of inflam-
ACKNOWLEDGMENTS mation–shape of the association according to
in early pregnancy and subsequent risk of pre-
We gratefully acknowledge the contribution of term delivery. Clin Biochem 2007;40:330-5. sex and body mass index. Alcohol Alcohol
general practitioners, hospitals, midwives, and 15. Jaddoe VW, van Duijn CM, van der Heijden 2010;45:119-25.
pharmacies in Rotterdam. AJ, et al. The Generation R Study: design and 29. Fredrikson GN, Hedblad B, Nilsson JA, Alm
cohort update until the age of 4 years. Eur J R, Berglund G, Nilsson J. Association between
Epidemiol 2008;23:801-11. diet, lifestyle, metabolic cardiovascular risk fac-
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1. Gabay C, Kushner I. Acute-phase proteins The Generation R Study Biobank: a resource for tabolism 2004;53:1436-42.
and other systemic responses to inflammation. epidemiological studies in children and their 30. Visser M, Bouter LM, McQuillan GM, Wener
N Engl J Med 1999;340:448-54. parents. Eur J Epidemiol 2007;22:917-23. MH, Harris TB. Elevated C-reactive protein lev-

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els in overweight and obese adults. JAMA 32. Berg AH, Scherer PE. Adipose tissue, in- 34. Smith GD, Ebrahim S. Mendelian random-
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31. Wee CC, Mukamal KJ, Huang A, Davis Res 2005;96:939-49. Int J Epidemiol 2004;33:30-42.
RB, McCarthy EP, Mittleman MA. Obesity and 33. Steegers-Theunissen RP, Steegers EA. Nu- 35. Nohr EA, Frydenberg M, Henriksen TB, Ol-
C-reactive protein levels among white, black, trient-gene interactions in early pregnancy: a sen J. Does low participation in cohort studies
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875-80. prod Biol 2003;106:115-7.

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SUPPLEMENTARY FIGURE S1
Flowchart of study participants

Ernst. C-reactive protein levels in pregnancy and fetal growth. Am J Obstet Gynecol 2011.

132.e9 American Journal of Obstetrics & Gynecology AUGUST 2011


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SUPPLEMENTARY TABLE S1
Associations of maternal characteristics with C-reactive
protein levels in early pregnancy
Characteristic n ⴝ 6016 C-reactive protein, mg/L
Maternal age, y
.....................................................................................................................................................................................................................................
⬍20 n ⫽ 204 3.42 (0.51–21.00)
.....................................................................................................................................................................................................................................
20-24.9 n ⫽ 965 4.61 (0.70–27.62)
.....................................................................................................................................................................................................................................
25-29.9 n ⫽ 1673 4.68 (0.60–27.01)
.....................................................................................................................................................................................................................................
30-34.9 n ⫽ 2337 4.12 (0.60–25.21)
.....................................................................................................................................................................................................................................
35-39.90 n ⫽ 759 4.18 (0.60–23.50)
.....................................................................................................................................................................................................................................
ⱖ40 n ⫽ 78 4.73 (1.13–21.48)
.....................................................................................................................................................................................................................................
P for trend .127
.....................................................................................................................................................................................................................................
Adjusted P for trend .475
..............................................................................................................................................................................................................................................
2
Maternal body mass index at intake, kg/m
.....................................................................................................................................................................................................................................
⬍19.9 n ⫽ 542 2.78 (0.35–17.92)
.....................................................................................................................................................................................................................................
20-24.9 n ⫽ 3260 3.54 (0.60–20.75)
.....................................................................................................................................................................................................................................
25-29.9 n ⫽ 1453 5.58 (1.00–25.22)
.....................................................................................................................................................................................................................................
30-34.9 n ⫽ 470 8.45 (1.98–29.92)
.....................................................................................................................................................................................................................................
ⱖ35 n ⫽ 229 10.87 (1.50–43.02)
.....................................................................................................................................................................................................................................
Missing n ⫽ 62 4.92 (0.51–21.53)
.....................................................................................................................................................................................................................................
P for trend ⬍ .001
.....................................................................................................................................................................................................................................
Adjusted P for trend ⬍ .001
..............................................................................................................................................................................................................................................
Parity
.....................................................................................................................................................................................................................................
0 n ⫽ 3412 3.84 (0.60–23.07)
.....................................................................................................................................................................................................................................
1 n ⫽ 1797 4.67 (0.60–28.21)
.....................................................................................................................................................................................................................................
ⱖ2 n ⫽ 756 6.15 (0.99–27.10)
.....................................................................................................................................................................................................................................
Missing n ⫽ 51 5.66 (0.40–36.83)
.....................................................................................................................................................................................................................................
P for trend ⬍ .001
.....................................................................................................................................................................................................................................
Adjusted P for trend ⬍ .001
..............................................................................................................................................................................................................................................
Highest completed educational level
.....................................................................................................................................................................................................................................
Primary school n ⫽ 549 5.40 (0.50–30.22)
.....................................................................................................................................................................................................................................
Secondary school n ⫽ 2534 4.75 (0.70–26.46)
.....................................................................................................................................................................................................................................
Higher education n ⫽ 2505 3.62 (0.60–22.34)
.....................................................................................................................................................................................................................................
Missing n ⫽ 428 5.40 (0.67–32.60)
.....................................................................................................................................................................................................................................
P for trend ⬍ .001
.....................................................................................................................................................................................................................................
Adjusted P for trend ⬍ .001
..............................................................................................................................................................................................................................................
Ernst. C-reactive protein levels in pregnancy and fetal growth. Am J Obstet Gynecol 2011. (continued )

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SUPPLEMENTARY TABLE S1
Associations of maternal characteristics with C-reactive
protein levels in early pregnancy (continued)
Characteristic n ⴝ 6016 C-reactive protein, mg/L
Ethnic background
.....................................................................................................................................................................................................................................
European n ⫽ 3502 3.95 (0.60–24.50)
.....................................................................................................................................................................................................................................
Non-European n ⫽ 2171 4.85 (0.60–27.07)
.....................................................................................................................................................................................................................................
Missing n ⫽ 343 5.41 (0.70–33.43)
.....................................................................................................................................................................................................................................
P trend ⬍ .001
.....................................................................................................................................................................................................................................
Adjusted P trend .103
.....................................................................................................................................................................................................................................
Smoking
.....................................................................................................................................................................................................................................
Not n ⫽ 3865 4.23 (0.60–26.04)
.....................................................................................................................................................................................................................................
First trimester only n ⫽ 480 3.95 (0.60–22.09)
.....................................................................................................................................................................................................................................
Continued n ⫽ 908 4.60 (0.60–22.13)
.....................................................................................................................................................................................................................................
Missing n ⫽ 763 4.84 (0.70–28.93)
.....................................................................................................................................................................................................................................
P for trend .048
.....................................................................................................................................................................................................................................
Adjusted P for trend .956
..............................................................................................................................................................................................................................................
Alcohol consumption
.....................................................................................................................................................................................................................................
Not n ⫽ 2424 4.79 (0.60–26.18)
.....................................................................................................................................................................................................................................
First trimester only n ⫽ 792 4.04 (0.70–22.25)
.....................................................................................................................................................................................................................................
Continued n ⫽ 2065 3.80 (0.74–24.10)
.....................................................................................................................................................................................................................................
Missing n ⫽ 735 4.86 (0.70–30.30)
.....................................................................................................................................................................................................................................
P for trend ⬍ .001
.....................................................................................................................................................................................................................................
Adjusted P for trend .095
..............................................................................................................................................................................................................................................
Values are presented as geometric means (95% range).
Values are based on multivariate linear regression models with adjustment for all maternal characteristics from this table.
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SUPPLEMENTARY FIGURE S2
Correlation of gestational age and maternal BMI with CRP levels

Plots represent correlation of gestational age at blood collection and BMI at intake with CRP levels,
respectively. CRP was not normally distributed and therefore log transformation was performed.
BMI, body mass index; CRP, C-reactive protein.
Ernst. C-reactive protein levels in pregnancy and fetal growth. Am J Obstet Gynecol 2011.

AUGUST 2011 American Journal of Obstetrics & Gynecology 132.e12