The Journal of Allergy and Clinical Immunology: In Practice
Original ArticleThe Association of Prenatal C-Reactive Protein Levels With Childhood Asthma and Atopy
Introduction
The development of childhood atopy has well-described contributions from genetic and postnatal environmental factors.1,2 Increasingly, a link between the prenatal environment, maternal immune response, and allergic disease has also been recognized.3, 4, 5, 6 Maternal obesity, smoking, diet, vitamin D insufficiency, and socioeconomic status are examples of prenatal factors that have been associated with offspring atopy.2,7, 8, 9 Several of these maternal factors have also been associated with increased plasma C-reactive protein (CRP), a biomarker of systemic inflammation.10, 11, 12, 13
Previous cohort studies have demonstrated an association between elevated maternal proinflammatory cytokines or CRP at a single time point in pregnancy and offspring asthma, wheezing, and atopy.6,14, 15, 16 We sought to replicate findings from the previous literature as well as to deepen understanding by providing a more longitudinal description of CRP in early and late pregnancy and its association with maternal health and offspring atopy. Further characterization of this relationship and identification of modifiable sources of maternal prenatal inflammation could lead to effective interventions to decrease offspring atopic risk.
We hypothesized that increased maternal inflammation during pregnancy is associated with childhood asthma, eczema, and allergic rhinitis, and might mediate associations between maternal characteristics and offspring outcomes. We analyzed serial prenatal measurements of plasma CRP in a large, diverse birth cohort followed prospectively for outcomes of offspring asthma, eczema, and allergic rhinitis.
Section snippets
Study design and participants
We performed an ancillary analysis of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized controlled trial of vitamin D in pregnant women that randomized 881 women to 4400 international units or 400 international units vitamin D daily.17 Inclusion criteria required that participants were nonsmoking at enrollment and had a personal or biologic father’s history of asthma or atopy. Written informed consent was obtained from participants, and the study was approved by the
Baseline characteristics
From the VDAART cohort, 528 of the 816 maternal-offspring pairs had complete prenatal biomarker data in early and late pregnancy. Offspring outcome data at age 6 years were missing for 6 pairs, yielding a final study sample of 522 pairs that was comparable to the overall VDAART cohort (Figure 1; see Table E3 in this article’s Online Repository at www.jaci-inpractice.org).
Offspring with asthma were more likely than those without asthma to have younger mothers (mean, 26 vs 28 years; P < .001),
Discussion
In this large and diverse cohort, early and late prenatal CRP and increasing CRP over pregnancy were associated with offspring asthma by age 6 years. Previous studies have reported associations between prenatal CRP and early-life wheezing or asthma.15,16 Morales et al15 found that higher first-trimester CRP was associated with offspring recurrent wheezing between age 6 and 14 months. Lapin et al16 reported a positive association between a single log-transformed prenatal CRP measurement from
Conclusions
Increased systemic inflammation and innate immunity dysregulation, as marked by elevated prenatal CRP, is associated with childhood asthma. Failure to control maternal inflammation during pregnancy may increase the risk of atopic asthma more than nonatopic asthma. Through mediation analysis, we found evidence that vitamin D sufficiency in early pregnancy and normal prepregnancy BMI are protective against elevated prenatal CRP, suggesting that interventions to optimize maternal health and
Acknowledgments
We thank the study coordinators and participants of the VDAART for their contributions and support.
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We acknowledge funding support from the National Health, Lung and Blood Institute (NHLBI) (grant no. R01 HL091528) and from the National Institutes of Health Office of the Director (grant no. UH3 OD023268 to S.T.W. and A.A.L.). Y.-C.S.C. is supported by the NHLBI (grant nos. T-32 HL007427 and T-32 AI007306). K.A.L.-S. is supported by the NHLBI (grant no. K08HL148178). H.M. is supported by the NHLBI (grant no. K01HL146977-01A1). R.S.K. is supported by the NHLBI (grant no. K01HL146980). H.M.K. is supported by the Jane and Aatos Erkko Foundation, the Paulo Foundation, and the Pediatric Reuter Foundation.
Conflicts of interest: L. B. Bacharier reports grants from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases and National Heart, Lung, and Blood Institute (NHLBI); personal fees from GlaxoSmithKline, Genentech/Novartis, DBV Technologies, Teva, Boehringer Ingelheim, AstraZeneca, WebMD/Medscape, Sanofi, Regeneron, Vectura, Circassia, Kinaset, Vertex, and OM Pharma; and royalties from Elsevier outside the submitted work. R. S. Zeiger is a consultant for AstraZeneca, DBV Technologies, Genentech, Inc, GlaxoSmithKline, Novartis, and Regeneron, and has received research support from Aerocrine, AstraZeneca, Genentech, Inc, GlaxoSmithKline, MedImmune, Merck, NHLBI, Quest Diagnostics, and Teva Pharmaceuticals. G. T. O’Connor has been compensated for speaking at a conference supported by Menarini, Inc, and for serving on a Data and Safety Monitoring Committee for Dicerna, Inc. S. T. Weiss and A. A. Litonjua have received royalties from UpToDate, Inc. The rest of the authors declare that they have no relevant conflicts of interest.