Objective To determine the combined effect of 60 genetic variants (single nucleotide polymorphisms, SNPs), previously identified as being associated with birth weight, on fetal growth and placental haemodynamics throughout pregnancy.
Design Prospective birth cohort (Generation R Study).
Setting General multiethnic population.
Participants 5374 singleton liveborn children with genome-wide association arrays and fetal growth data.
Methods Longitudinal and cross-sectional analyses of a genetic score of the total number of birth weight–increasing alleles across the 59 available SNPs and repeated fetal growth and haemodynamic measures.
Main outcome measures SD scores (SDS) of fetal weight, (femur) length, head circumference, umbilical artery pulsatility index, uterine artery mean resistance index and placental weight, in different periods of pregnancy until birth.
Results In longitudinal analyses, the effect of the genetic score on the fetal growth measures increased throughout pregnancy (p<0.001). At 20 weeks of gestation, the genetic score was not associated with any of the fetal growth measures, whereas at 30 weeks it was associated with all. The strongest effects were observed at birth: per SD increase in genetic score, birth weight increased by 0.15 SDS (95% confidence interval: 0.13 to 0.18), birth length by 0.12 SDS (0.08 to 0.19) and head circumference by 0.08 SDS (0.05 to 0.12). The genetic score was not associated with placental haemodynamics, but was associated with a 14 g (10 to 18) increase in placental weight per SDS increase in genetic score.
Conclusions Our results suggest that genetic variants related to birth weight exert their combined effect on fetal growth from second half of pregnancy onwards and have no effect on placental haemodynamics.
- fetal growth
- genetic variants
- genetic risk score
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Contributors MJV contributed to the design of the study, analysed and interpreted the data, and drafted the manuscript. RG contributed to the design of the study and assisted with the analyses and interpretation of data and writing of the manuscript. KM assisted with the analyses and graphs, and writing of the manuscript. IR contributed to the design of the manuscript, interpretation of the data and critically revised the manuscript. EAPS contributed to data collection, design of the study, interpretation of the data and critically revised the manuscript. VJ contributed to the organisation of data collection, the design of the study, interpretation of the data, and critical revision of the manuscript. JF contributed to data collection, the design of the study, writing of the manuscript, interpretation of the data and critical revisions for intellectual content. All authors approved the final version of the manuscript.
Funding The general design of the Generation R Study is made possible by financial support from the Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam, the Netherlands Organisation for Health Research and Development and the Ministry of Health, Welfare and Sport. VJ received a grant from the Netherlands Organisation for Health Research and Development (VIDI 016.136.361) and a Consolidator Grant from the European Research Council (ERC-2014-CoG-648916). The project received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreements no. 633 595 (DynaHEALTH) and no. 733 206 (LifeCycle).
Disclaimer The funding sources had no involvement in study design, in the collection, analysis and interpretation of the data, in writing of the report nor in the decision to submit the article for publication.
Competing interests None declared.
Patient consent for publication Obtained.
Ethics approval Medical Ethics Committee of Erasmus MC, Rotterdam, the Netherlands (MEC 198.782/2001/31).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request.
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