Is ovarian hyperstimulation associated with higher blood pressure in 4-year-old IVF offspring? Part II: an explorative causal inference approach.

In this assessor-blinded follow-up study, 194 children were assessed. The attrition rate until the 4-year-old assessment was 10%. The authors measured blood pressure and anthropometrics of 4-year-old singletons born following COH-IVF (n = 63), or born following modified natural cycle IVF (MNC-IVF, n = 52) or born to subfertile couples who conceived naturally (Sub-NC, n = 79). Primary outcome measures were the systolic blood pressure (SBP) and diastolic blood pressure (DBP) percentiles. Anthropometrics included triceps and subscapular skinfold thickness. Causal inference search algorithms and structural equation modeling were applied. Explorative analyses suggested a direct effect of COH on SBP percentiles and on subscapular skinfold thickness. This hypothesis needs confirmation with additional, preferably larger, studies. Search algorithms were used as explorative tools to generate hypotheses on the causal mechanisms underlying fertility treatment, blood pressure, anthropometrics and other variables. More studies using larger groups are needed to draw firm conclusions. These findings are in line with other studies describing adverse effects of IVF on cardiometabolic outcome, but this is the first study suggesting a causal mechanism underlying this association. Perhaps ovarian hyperstimulation negatively influences cardiometabolic outcome via changes in the early environment of the oocyte and/or embryo, possibly resulting in epigenetic modifications of key metabolic systems that are involved in BP regulation. Future research needs to confirm the role of ovarian stimulation in poorer cardiometabolic outcome and should investigate the underlying mechanisms. The proposed causal models provide research hypotheses to be tested with new data from preferably larger studies.