Placental growth plays a key role in the link between maternal glucose levels in pregnancy and risk of preeclampsia

Preeclampsia is a serious condition affecting 2-4% of pregnancies globally. However, it is more common in pregnancies with diabetes (e.g. 10-20% in Type 1 diabetes) than in pregnancies without diabetes. In the general population, higher maternal fasting glucose levels are observationally associated with higher risk of preeclampsia, but whether the relationship is causal is unknown. Based on previous research, we hypothesise that higher fasting glucose increases placental weight, likely through fetal insulin mediated growth, and higher placental weight increases the risk of preeclampsia. We used data from published genome-wide association studies on fasting glucose (N=281,416), placental weight (Nfetal=65,405, Nmaternal=61,228) and preeclampsia (Nfetal=377,975, Nmaternal=723,181) and individual level data from the Exeter Family Study of Childhood Health (N=948) and the Avon Longitudinal Study of Parents and Children (N=5,214). We compared observational multivariable regression analysis with Mendelian Randomization (MR), an analytical approach that uses genetic variants to estimate causal effects of exposures (e.g. fasting glucose) on outcomes (e.g. risk of preeclampsia). We found that genetically instrumenting a 1mmol/l higher fasting glucose caused a higher placental weight of 44.16g (95%CI: [29.82,58.49]). Furthermore, we showed that fetal genetic predisposition to higher placental weight increased the risk of preeclampsia (OR=1.99, 95% CI: [1.25, 3.19]). Using the two-step MR method, we estimated that a maternal genetic predisposition to higher fasting glucose increases the risk of preeclampsia through increasing placental weight with an OR of 1.26 (95% CI: [1.05,1.49]). We found evidence for a causal effect of higher maternal fasting glucose levels on risk of preeclampsia, and our results are consistent with this effect being mediated via placental weight. Further well-powered studies are needed to confirm the causal relationship between higher maternal fasting glucose and preeclampsia. If confirmed, our findings suggest research focusing on fetal insulin may help elucidate preeclampsia disease mechanisms. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSObservational analysis from the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study showed that 1 standard deviation higher maternal fasting glucose was associated with a 1.21 (95% confidence interval: [1.13-1.29]) higher odds of preeclampsia. However, whether this relationship is causal is unknown. It is known that maternal glucose crosses the placenta, but maternal insulin does not. The glucose reaching the fetus, stimulates fetal insulin secretion which acts as a potent growth factor for both the fetus and placenta. Moreover, insights from genetic analyses recently revealed that a higher placental weight is causally linked to higher preeclampsia risk. Added value of this studyBuilding on the above findings, we hypothesised that higher maternal glucose results in increased fetal insulin-mediated placental growth that increases the risk of preeclampsia. To our knowledge, this is the first study to investigate the relationships between maternal fasting glucose, placental weight and preeclampsia in the same study. The use of genetic data allows us to compare observational findings with causal analyses. Our results provide evidence that greater placental growth is on the causal pathway between higher maternal fasting glucose levels in pregnancy and risk of preeclampsia. Therefore, we highlight a potential additional contributor to the diabetes-preeclampsia link: fetal insulin mediated growth of the placenta. Implications of all the available evidenceOur findings contribute to an understanding of why preeclampsia is more prevalent in pregnancies affected by diabetes. A better understanding of causal biological processes underlying the pathology of preeclampsia is important for the development of treatment and optimal care for pregnant women. If confirmed, our results support that measuring and optimising maternal glucose levels in pregnancies will be an important tool in reducing preeclampsia risk and suggest that markers of placental growth could help with risk stratification in the future.