title: Is ovarian hyperstimulation associated with higher blood pressure in 4-year-old IVF offspring? Part II: an explorative causal inference approach.
abstract: OBJECTIVE
  What causal relationships underlie the associations between ovarian stimulation, the IVF procedure, parental-, fertility- and child characteristics, and blood pressure (BP) and anthropometrics of 4-year-old IVF children?
  
  
  CONCLUSIONS
  Causal models compatible with the data suggest the presence of positive direct effects of controlled ovarian hyperstimulation as applied in IVF (COH-IVF) on systolic blood pressure (SBP) percentiles and subscapular skinfold thickness.
  
  
  BACKGROUND
  Increasing evidence suggests that IVF is associated with higher blood pressure and altered body fat distribution in offspring, but underlying mechanisms describing the causal relationships between the variables are largely unknown.
  
  
  METHODS
  In this assessor-blinded follow-up study, 194 children were assessed. The attrition rate until the 4-year-old assessment was 10%.
  
  
  METHODS
  We 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 SBP and diastolic blood pressure (DBP) percentiles. Anthropometrics included triceps and subscapular skinfold thickness. Causal inference search algorithms and structural equation modeling were applied.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  Our 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. Our proposed causal models provide research hypotheses to be tested with new data from preferably larger studies.
  
  
  BACKGROUND
  The authors have no conflicts of interest to declare. The study was supported by the University Medical Center Groningen, the Cornelia Foundation and the school for Behavioral- and Cognitive Neurosciences. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report.
authors.affiliation: Department Epidemiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen 9713 GZ, The Netherlands.
authors.forename: Sacha
authors.initials: S
authors.lastname: La Bastide-Van Gemert
authors.forename: Jorien
authors.initials: J
authors.lastname: Seggers
authors.forename: Maaike L
authors.initials: ML
authors.lastname: Haadsma
authors.forename: Maas Jan
authors.initials: MJ
authors.lastname: Heineman
authors.forename: Karin J
authors.initials: KJ
authors.lastname: Middelburg
authors.forename: Tessa J
authors.initials: TJ
authors.lastname: Roseboom
authors.forename: Pamela
authors.initials: P
authors.lastname: Schendelaar
authors.forename: Mijna
authors.initials: M
authors.lastname: Hadders-Algra
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Van den Heuvel
mesh_terms: D000465:Algorithms; D001794:Blood Pressure; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000209:etiology*; D008297:Male; D010062:Ovulation Induction / Q000009:adverse effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012885:Skinfold Thickness
keywords: IVF; blood pressure; cardiometabolic outcome; causality; ovarian hyperstimulation