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Impaired pulmonary function mediates the impact of preterm birth on later-life stroke: a 2-step, multivariable Mendelian randomization study
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Xingzhi Guo, Peng Tang, Chen Hou, Yue Liu, Rui Li
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Epidemiol Health. 2023;45:e2023031. Published online March 3, 2023
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DOI: https://doi.org/10.4178/epih.e2023031
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 Abstract
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Abstract
OBJECTIVES
Observational studies have suggested an association between preterm birth and stroke in late adulthood, but it remains unclear whether the association is causal. The purpose of this study was to evaluate the causal effects of gestational age on stroke and to determine the pathophysiological mechanisms underlying the causal associations.
METHODS Two-sample Mendelian randomization (MR) was performed to assess the causal effects of fetal gestational duration, early preterm birth (EPB), preterm birth, or postterm birth on stroke and its subtypes. Two-step Mendelian randomization (TSMR) and multivariable Mendelian randomization (MVMR) were additionally used to determine the role of common stroke risk factors, including cardiovascular diseases, hypertension, pulmonary impairment, inflammation, and metabolic diseases, in mediating the causal associations between gestational age and stroke and its subtypes.
RESULTS Genetically predicted EPB increased the risk of cardioembolic stroke (CES; odds ratio [OR], 1.115; 95% confidence interval [CI], 1.036 to 1.200; p=0.004) and large artery stroke (LAS; OR, 1.131; 95% CI, 1.031 to 1.241; p=0.009). The TSMR results showed that EPB was associated with a lower forced expiratory volume in the first second and forced vital capacity ratio (FEV1/FVC) (β=-0.020; 95% CI, -0.035 to -0.005; p=0.009), which increased the risk of CES and LAS. Further MVMR analysis showed that the associations between EPB and stroke disappeared after adjustment for FEV1/FVC.
CONCLUSIONS Our data demonstrate that EPB is causally associated with an elevated risk of CES and LAS, and that pulmonary dysfunction mediates the causal impact of EPB on CES and LAS.
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Summary
Key Message
Genetically predicted early preterm birth (EPB) is significantly associated with an increased risk of cardioembolic stroke (CES) and large artery stroke (LAS). Further multivariable Mendelian randomization analysis demonstrates that pulmonary impairment mediates the causal impact of EPB on CES and LAS in adulthood.
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Citations
Citations to this article as recorded by  - Causal associations of circulating Helicobacter pylori antibodies with stroke and the mediating role of inflammation
Xingzhi Guo, Peng Tang, Xin Zhang, Rui Li
Inflammation Research.2023; 72(6): 1193. CrossRef - Methodological approaches, challenges, and opportunities in the application of Mendelian randomisation to lifecourse epidemiology: A systematic literature review
Grace M. Power, Eleanor Sanderson, Panagiota Pagoni, Abigail Fraser, Tim Morris, Claire Prince, Timothy M. Frayling, Jon Heron, Tom G. Richardson, Rebecca Richmond, Jessica Tyrrell, Nicole Warrington, George Davey Smith, Laura D. Howe, Kate M. Tilling
European Journal of Epidemiology.2023;[Epub] CrossRef
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