title: Increased time to pregnancy is associated with less optimal neurological condition in 4-year-old singletons, in vitro fertilization itself is not.
abstract: OBJECTIVE
  Does ovarian hyperstimulation, the in vitro procedures required for in vitro fertilization (IVF)/ intracytoplasmic sperm injection or the combination of both, affect the neurological outcome of 4-year-old singletons?
  
  
  CONCLUSIONS
  Ovarian hyperstimulation, the in vitro procedure and the combination of both, were not associated with the worse neurological outcome in 4-year-old singletons.
  
  
  BACKGROUND
  Assisted reproduction techniques (ARTs) are not associated with neurological dysfunction during the first post-natal years; however, effects on the long-term neurological outcome are still inconclusive. An increased time to pregnancy (TTP, a proxy for the severity of subfertility) has been associated with a less optimal neurological condition at age 2. The present study focuses on the neurodevelopmental outcome of 4-year-old ART-offspring.
  
  
  METHODS
  Longitudinal, prospective follow-up study.
  
  
  METHODS
  Four-year-old singletons born to subfertile parents (subfertile group, n = 195), including singletons born after controlled ovarian hyperstimulation IVF (COH-IVF, n = 63), modified natural cycle IVF (MNC-IVF, n = 53) and natural conception (Sub-NC, n = 79). Data on underlying cause of subfertility and TTP were present. In addition, we assessed newly recruited 4-year-old singletons born to fertile parents after natural conception (reference group, n = 98). Neurological development was evaluated with the neurological examination according to Hempel, resulting in a neurological optimality score (NOS), a fluency score and the occurrence of the clinically relevant form of minor neurological dysfunction (complex MND). The primary outcome was the fluency score, as fluency of movements is easily reduced by subtle brain dysfunction. Data were analysed with univariable and multivariable regression analyses, in which special attention was paid to sex differences in the neurological outcome.
  
  
  RESULTS
  The fluency score, NOS and the prevalence of complex MND were similar in COH-IVF, MNC-IVF and Sub-NC children. The neurological condition of children born to subfertile parents was similar to that of children of fertile parents and was independent of the underlying cause of subfertility. No statistically significant associations were found between TTP and the fluency score and NOS. However, a positive correlation was found between TTP and the prevalence of complex MND (TTP in years, adjusted odds ratio [OR] [95% confidence interval, CI]: 1.207 [1.038 to 1.404], P = 0.014); a correlation which could be attributed to girls, in whom an evident positive correlation was present (adjusted OR [95% CI]: 1.542 [1.161 to 2.047], P = 0.003). A similar association was absent in boys.
  
  
  CONCLUSIONS
  The prospective design of our study and small post-natal attrition rate (9.3%) reduced potential selection bias based on the child's development or health. The assessors were blind to the mode of conception, except for the group of children born to fertile parents, which was newly recruited. The study lacks sufficient power to conclude firmly that increased TTP is associated with a higher prevalence of complex MND.
  
  
  CONCLUSIONS
  Our study suggests that the severity of subfertility, rather than its simple presence or components of IVF treatment, affects the neurological outcome. Moreover, girls may be neurologically more vulnerable for the effect of severity of subfertility. The finding that the severity of subfertility may be the decisive factor rather than the presence of a history of subfertility per se corroborates previous reports. Our results cannot be generalized to multiples, as we studied singletons only.
  
  
  BACKGROUND
  The study was financially supported by the University Medical Center Groningen, grant number: 754510, the Junior Scientific Masterclass, the Postgraduate School Behavioural and Cognitive Neurosciences and the Cornelia Foundation, Groningen, The Netherlands. The authors have no conflicts of interest to declare.
authors.affiliation: Department of Paediatrics, Division Developmental Neurology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen GZ 9713, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Schendelaar
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen GZ 9713, The Netherlands.
authors.forename: E R
authors.initials: ER
authors.lastname: Van den Heuvel
authors.affiliation: Department of Obstetrics and Gynaecology, Academic Medical Center, Meibergdreef 9, Amsterdam AZ 1105, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Heineman
authors.affiliation: Department of Epidemiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen GZ 9713, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: La Bastide-Van Gemert
authors.affiliation: Department of Obstetrics and Gynaecology, Academic Medical Center, Meibergdreef 9, Amsterdam AZ 1105, The Netherlands.
authors.forename: K J
authors.initials: KJ
authors.lastname: Middelburg
authors.affiliation: Department of Paediatrics, Division Developmental Neurology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen GZ 9713, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Seggers
authors.affiliation: Department of Paediatrics, Division Developmental Neurology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, Groningen GZ 9713, The Netherlands m.hadders-algra@umcg.nl.
authors.forename: M
authors.initials: M
authors.lastname: Hadders-Algra
mesh_terms: D000328:Adult; D002657:Child Development; D002675:Child, Preschool; D005260:Female; D005307:Fertilization in Vitro / Q000009:adverse effects*; D005500:Follow-Up Studies; D006801:Humans; D008137:Longitudinal Studies; D009460:Neurologic Examination; D010062:Ovulation Induction / Q000009:adverse effects*; D061685:Time-to-Pregnancy
keywords: ART; IVF; neurodevelopmental outcome; ovarian hyperstimulation; subfertility