Inflammatory markers in pregnancy -identifying drivers in four large cohorts

Frederieke Gigase^1*Anna Suleri¹Elena Isaevska¹Anna-Sophie Rommel²Myrthe Boekhorst³Olga Dmitrichenko²Hanan El Marroun^1,4Eric Steegers⁵Manon H.J. Hillegers¹Ryan Muetzel^1,6Whitney Lieb⁷Charlotte A M Cecil^1,8,9Victor Pop¹⁰Michael Breen²Veerle Bergink^11,12,2Lot D De Witte^13,14,2

• ¹Department of Child and Adolescent Psychiatry, Erasmus Medical Center, Rotterdam, Netherlands
• ²Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, United States
• ³Department of Medical and Clinical Psychology, Tilburg University, Tilburg, Netherlands
• ⁴Department of Psychology, Education and Child Studies, School of Social and Behavioural Sciences, Erasmus University Rotterdam, Rotterdam, Netherlands
• ⁵Department of Obstetrics and Gynecology, Erasmus Medical Center, Rotterdam, Netherlands
• ⁶Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, Netherlands
• ⁷Department of Obstetrics, Gynecology and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York, United States
• ⁸Department of Epidemiology, Erasmus Medical Center, Rotterdam, Netherlands
• ⁹Department of Biomedical Data Sciences, Leiden University Medical Center (LUMC), Leiden, Netherlands
• ¹⁰Department of Medical and Clinical Psychology, Tilburg School of Social and Behavioral Sciences, Tilburg University, Tilburg, Netherlands
• ¹¹Department of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York, United States
• ¹²Department of Psychiatry, Erasmus Medical Center, Rotterdam, Netherlands
• ¹³Department of Human Genetics, Radboud University Medical Centre, Nijmegen, Gelderland, Netherlands
• ¹⁴Department of Psychiatry, Radboud University Medical Center, Nijmegen, Netherlands

Adaptations of the immune system throughout gestation have been proposed as important mechanisms regulating successful pregnancy. Dysregulation of the maternal immune system has been associated with adverse maternal and fetal outcomes. The design and interpretation of human biomarker studies require additional insights in the trajectories and drivers of peripheral immune markers. The current study mapped maternal inflammatory markers (C-reactive protein (CRP), interleukin (IL)-1β, IL-6, IL-17A, IL-23, interferon-γ) during pregnancy and investigated the impact of demographic, environmental and genetic drivers on maternal inflammatory marker levels in four multi-ethnic and socio-economically diverse population-based cohorts with more than 12,000 pregnant participants. Additionally, pregnancy inflammatory markers were compared to pre-pregnancy levels. Cytokines showed a high correlation with each other, but not with CRP.Inflammatory marker levels showed high variability between individuals, yet high concordance within an individual over time during and pre-pregnancy. Pre-pregnancy body mass index (BMI) explained ~ 9.6% of the variance in CRP, but less than 1% of the variance in cytokines. The polygenic score of CRP was the best predictor of variance in CRP (14.1%). Gestational age and previously identified inflammation drivers, including tobacco use and parity, explained less than 1% of variance in both cytokines and CRP. Our findings corroborate differential underlying regulatory mechanisms of CRP and cytokines and are suggestive of an individual inflammatory marker baseline which is, in part, genetically driven.