title: The phenotype of an IVF child is associated with peri-conception measures of follicular characteristics and embryo quality.
abstract: OBJECTIVE
  Are childhood measures of phenotype associated with peri-conception parental, IVF treatment and/or embryonic characteristics of IVF children?
  
  
  CONCLUSIONS
  Birthweight, childhood body mass index (BMI) and height of pre-pubertal IVF children were strongly associated with peri-conception factors, including follicular and embryonic characteristics.
  
  
  BACKGROUND
  A growing number of studies have identified a range of phenotypic differences between IVF and naturally conceived pre-pubertal children; for example, birthweights are lower following a fresh compared with a thawed embryo transfer.
  
  
  METHODS
  This retrospective cohort study included IVF children (n = 96) born at term (>37 weeks) after a singleton pregnancy from the transfer of either fresh or thawed embryos in New Zealand. Between March 2004 and November 2008, these children were subjected to clinical assessment before puberty.
  
  
  METHODS
  Clinical assessment provided anthropometric measures of children aged 3.5-11 years old. Peri-conception factors (n = 36) derived retrospectively from parental, treatment, laboratory and embryonic variables (n = 69) were analysed using multiple stepwise regression with respect to standard deviation scores (SDSs) of the birthweight, mid-parental corrected BMI and height of the IVF children. Data from children conceived from fresh (n = 60) or thawed (n = 36) embryos, that met inclusion criteria and had high-quality data with >90% completeness, were analysed.
  
  
  RESULTS
  Embryo treatment at transfer was identified as a predictor of birthweight with thawed embryos resulting in heavier birthweights than fresh embryos [P = 0.02, 95% confidence interval (CI) fresh minus thawed: -1.047 to -0.006]. Birthweight SDS was positively associated with mid-parental corrected BMI SDS (P = 0.003, slope 0.339 ± 0.100). Four factors were related (P < 0.05) to mid-parental corrected height SDS. In particular, child height was inversely associated with the diameter of lead follicles at oocyte retrieval (P < 0.0001, slope -0.144 ± 0.040) and with the quality score of embryos at transfer (P = 0.0008, slope -0.425 ± 0.157), and directly associated with the number of follicles retrieved (P = 0.05, slope 1.011 ± 0.497). Child height was also positively associated with the transfer of a fresh as opposed to thawed embryo (P < 0.001, 95% CI 0.275-0.750).
  
  
  CONCLUSIONS
  More than one embryo was transferred in most cycles so mean development and quality data were used. The large number of variables measured was on a relatively small sample size. Large cohorts from multiple clinics using a variety of treatment protocols and embryology methods are needed to confirm the associations identified and ultimately to test these factors as possible predictors of phenotype.
  
  
  CONCLUSIONS
  This is the first study to directly associate peri-conception measures of IVF treatment with a pre-pubertal child's phenotype. Demonstration that peri-conception measures relate to a pre-pubertal child's phenotype extends the range of factors that may influence growth and development. These findings, if corroborated by larger studies, would provide invaluable information for practitioners, who may want to consider the impact of ovarian stimulation protocols as well as the quality of the embryo transferred on a child's growth and development, in addition to their impact on pregnancy rate.
  
  
  BACKGROUND
  This work was supported by grants from the National Research Centre of Growth and Development New Zealand (grant 3682065) and the Australasian Paediatric Endocrine Group (APEG; grant 3621994), as well as a fellowship from Fertility Associates New Zealand awarded to M.P.G. In terms of competing interest, J.C.P is a shareholder of Fertility Associates. M.P.G. currently holds the position of Merck Serono Lecturer in Reproductive Biology. W.S.C. and P.L.H. have also received grants and non-financial support from Novo Nordisk, as well as personal fees from Pfizer that are unrelated to the current study. The other authors have no conflict of interest to declare.
authors.affiliation: The Liggins Institute and Gravida (National Research Centre for Growth and Development), University of Auckland, Auckland 1023, New Zealand AgResearch Ltd., Ruakura Research Centre, Hamilton 3240, New Zealand mark.green@unimelb.edu.au.
authors.forename: M P
authors.initials: MP
authors.lastname: Green
authors.affiliation: The Liggins Institute and Gravida (National Research Centre for Growth and Development), University of Auckland, Auckland 1023, New Zealand.
authors.forename: F
authors.initials: F
authors.lastname: Mouat
authors.affiliation: The Liggins Institute and Gravida (National Research Centre for Growth and Development), University of Auckland, Auckland 1023, New Zealand.
authors.forename: H L
authors.initials: HL
authors.lastname: Miles
authors.affiliation: The Liggins Institute and Gravida (National Research Centre for Growth and Development), University of Auckland, Auckland 1023, New Zealand AgResearch Ltd., Ruakura Research Centre, Hamilton 3240, New Zealand.
authors.forename: A B
authors.initials: AB
authors.lastname: Pleasants
authors.affiliation: AgResearch Ltd., Ruakura Research Centre, Hamilton 3240, New Zealand.
authors.forename: H V
authors.initials: HV
authors.lastname: Henderson
authors.affiliation: The Liggins Institute and Gravida (National Research Centre for Growth and Development), University of Auckland, Auckland 1023, New Zealand.
authors.forename: P L
authors.initials: PL
authors.lastname: Hofman
authors.affiliation: Fertility Associates, Auckland 1051, New Zealand.
authors.forename: J C
authors.initials: JC
authors.lastname: Peek
authors.affiliation: The Liggins Institute and Gravida (National Research Centre for Growth and Development), University of Auckland, Auckland 1023, New Zealand.
authors.forename: W S
authors.initials: WS
authors.lastname: Cutfield
mesh_terms: D001724:Birth Weight / Q000502:physiology*; D002648:Child; D002657:Child Development / Q000502:physiology*; D002675:Child, Preschool; D015331:Cohort Studies; D004624:Embryo Transfer / Q000379:methods*; D005260:Female; D005307:Fertilization in Vitro / Q000379:methods*; D006801:Humans; D008297:Male; D006080:Ovarian Follicle / Q000502:physiology*; D010062:Ovulation Induction / Q000379:methods; D010641:Phenotype; D011247:Pregnancy; D012189:Retrospective Studies
keywords: IVF child; height; measures; peri-conception; phenotype