Interrogating the causal effects of maternal circulating CRP on gestational duration and birth weight

Background C-reactive protein (CRP) is an acute-phase marker of inflammation. Previous epidemiological studies have associated elevated maternal CRP levels during pregnancy with preterm birth risk and lower birth weight. However, the causal relationships behind these observed associations are not clear. Methods and Findings We utilized phenotype and genotype data on 10,734 mother/child pairs of European ancestry collected from six birth cohorts. We performed two-sample multivariate Mendelian Randomization (MR) using maternal non-transmitted alleles to interrogate the causal effect of maternal CRP on gestational duration and birth weight. Based on the non-transmitted alleles of 55 CRP associated single nucleotide polymorphisms (SNPs), a unit increase in log-transformed maternal CRP level was associated with a reduction of 1.58 days (95% CI: 0.23, 2.94, P = 0.022) in gestational duration and a reduction of 76.3g (95% CI: 18.2, 134.4, P = 0.010) in birth weight. The magnitude of the association between genetically increased CRP and birth weight was reduced after adjusting for gestational age. Utilizing the effect estimates of CRP-associated SNPs on birth weight from the UK Biobank genome-wide association (GWA) summary results, our results suggested one unit of genetically increased maternal CRP was associated with a decrease of 50.1g (95% CI: 24.7, 75.5, P = 9.6E-5) of birth weight (unadjusted by gestational age). We validated the results using a single genetic variant (rs2794520) near the CRP gene, which is less prone to horizontal pleiotropy bias. Conclusions Increased maternal CRP levels appear to causally reduce gestational duration and birth weight. The effect of maternal CRP on birth weight is partially due to its effect on gestational duration. The estimated causal effect sizes are consistent with previous epidemiological reports and this triangulation increases confidence in these results being causal. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number R01HD101669. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. GZ is supported by the Burroughs Wellcome Fund (Grant 10172896), the March of Dimes Prematurity Research Center Ohio Collaborative and the Bill & Melinda Gates Foundation. The Norwegian Mother and Child Cohort Study (MoBa) is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), and NIH/NINDS (grant no. 1: UO1 NS 047537-01 and grant no. 2: UO1 NS 047537-06A1). The genotyping and analyses were supported by grants from Jane and Dan Olsson Foundation (Gothenburg, Sweden), Swedish Medical Research Council (2015-02559, 2019-01004), Norwegian Research Council/FUGE (grant no. 151918/S10, FRI-MEDBIO 249779, 547711, and 273291), March of Dimes (21-FY16-121), and the Burroughs Wellcome Fund Preterm Birth Research Grant (10172896) and by Swedish government grants to researchers in the public health sector (ALFGBG-717501, ALFGBG-507701, ALFGBG-426411 and ALFGBG-965353) to BJ. DAL is supported by a grant from the US National Institute of Health (R01 DK10324), an NIHR Senior Investigator Award (NF-0616-10102), a grant from the European Research Council (DevelopObese; 669545) and a grant from the British Heart Foundation (AA/18/7/34219). The UK Medical Research Council and Wellcome (grant ref: 102215/2/13/2) and the University of Bristol provide core support for ALSPAC. GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf) The DNBC data sets used for the analyses described in this manuscript were obtained from dbGaP at https://www.ncbi.nlm.nih.gov/gap/ through dbGaP accession number phs000103.v1.p1. The GWAS of Prematurity and its Complications study is one of the genome-wide association studies funded as part of the Gene Environment Association Studies (GENEVA) under the Genes, Environment and Health Initiative (GEI). The HAPO data sets used for the analyses described in this manuscript were obtained from dbGaP at https://www.ncbi.nlm.nih.gov/gap/ through dbGaP accession number phs000096.v4.p1. This study is part of the Gene Environment Association Studies initiative (GENEVA) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The GPN datasets used for the analyses described in this manuscript were obtained from dbGaP at https://www.ncbi.nlm.nih.gov/gap/ through dbGaP accession number phs000714.v1.p1. Samples and associated were provided by the NICHD-funded Genomic and Proteomic Network for Preterm Birth Research (GPN-PBR). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study involves reanalysis of existing data sets, and the analyses are consistent with the original consent agreements under which the genomic and phenotypic data were obtained. Therefore, additional ethics approval was not required. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript