title: Is ovarian hyperstimulation associated with higher blood pressure in 4-year-old IVF offspring? Part I: multivariable regression analysis.
abstract: OBJECTIVE
  Does ovarian hyperstimulation, the in vitro procedure, or a combination of these two negatively influence blood pressure (BP) and anthropometrics of 4-year-old children born following IVF?
  
  
  CONCLUSIONS
  Higher systolic blood pressure (SBP) percentiles were found in 4-year-old children born following conventional IVF with ovarian hyperstimulation compared with children born following IVF without ovarian hyperstimulation.
  
  
  BACKGROUND
  Increasing evidence suggests that IVF, which has an increased incidence of preterm birth and low birthweight, is associated with higher BP and altered body fat distribution in offspring but the underlying mechanisms are largely unknown.
  
  
  METHODS
  We performed a prospective, assessor-blinded follow-up study in which 194 children were assessed. The attrition rate up until the 4-year-old assessment was 10%.
  
  
  METHODS
  We measured BP and anthropometrics of 4-year-old singletons born following conventional IVF with controlled ovarian hyperstimulation (COH-IVF, n = 63), or born following modified natural cycle IV (MNC-IVF, n = 52), or born to subfertile couples who conceived naturally (Sub-NC, n = 79). Both IVF and ICSI were performed. Primary outcome measures were the SBP percentiles and diastolic BP (DBP) percentiles. Anthropometric measures included triceps and subscapular skinfold thickness. Several multivariable regression analyses were applied in order to correct for subsets of confounders. The value 'B' is the unstandardized regression coefficient.
  
  
  RESULTS
  SBP percentiles were significantly lower in the MNC-IVF group (mean 59, SD 24) than in the COH-IVF (mean 68, SD 22) and Sub-NC groups (mean 70, SD 16). The difference in SBP between COH-IVF and MNC-IVF remained significant after correction for current, early life and parental characteristics (B: 14.09; 95% confidence interval (CI): 5.39-22.79), whereas the difference between MNC-IVF and Sub-NC did not. DBP percentiles did not differ between groups. After correction for early life factors, subscapular skinfold thickness was thicker in the COH-IVF group than in the Sub-NC group (B: 0.28; 95% CI: 0.03-0.53).
  
  
  CONCLUSIONS
  Larger study groups are necessary to draw firm conclusions. An effect of gender or ICSI could not be properly investigated as stratifying would further reduce the sample size. We corrected for the known differences between MNC-IVF and COH-IVF but it is possible that the groups differ in additional, more subtle parental characteristics. In addition, we measured BP on 1 day only, had no control group of children born to fertile couples (precluding investigating effects of the underlying subfertility) and included singletons only. As COH-IVF is associated with multiple births we may have underestimated cardiometabolic problems after COH-IVF. Finally, multivariable regression analysis does not provide clear insight in the causal mechanisms and we have performed further explorative analyses.
  
  
  CONCLUSIONS
  Our findings are in line with other studies describing adverse effects of IVF on cardiometabolic outcome but this is the first study suggesting that ovarian hyperstimulation, as used in IVF treatments, could be a causative mechanism. Perhaps ovarian hyperstimulation negatively influences cardiometabolic outcome via changes in the early environment of the oocyte and/or embryo that result in epigenetic modifications of key metabolic systems that are involved in BP regulation. Future research needs to assess further the role of ovarian hyperstimulation in poorer cardiometabolic outcome and investigate the underlying mechanisms. The findings emphasize the importance of cardiometabolic monitoring of the growing number of children born following IVF.
  
  
  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 of Paediatrics, Division of Developmental Neurology - CA 85, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
authors.forename: Jorien
authors.initials: J
authors.lastname: Seggers
authors.forename: Maaike L
authors.initials: ML
authors.lastname: Haadsma
authors.forename: Sacha
authors.initials: S
authors.lastname: La Bastide-Van Gemert
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: Edwin R
authors.initials: ER
authors.lastname: Van den Heuvel
authors.forename: Mijna
authors.initials: M
authors.lastname: Hadders-Algra
mesh_terms: D001794:Blood Pressure; D002675:Child, Preschool; D005260:Female; D005307:Fertilization in Vitro / Q000379:methods; D005500:Follow-Up Studies; D006801:Humans; D016471:Ovarian Hyperstimulation Syndrome / Q000209:etiology*; D010062:Ovulation Induction / Q000009:adverse effects / Q000379:methods; D012044:Regression Analysis
keywords: IVF; assisted reproduction technology; blood pressure; cardiometabolic outcome; ovarian hyperstimulation