title: Large baby syndrome in singletons born after frozen embryo transfer (FET): is it due to maternal factors or the cryotechnique?
abstract: OBJECTIVE
  Are singletons born after frozen embryo transfer (FET) at increased risk of being born large for gestational age (LGA) and if so, is this caused by intrinsic maternal factors or related to the freezing/thawing procedures?
  
  
  CONCLUSIONS
  Singletons after FET have an increased risk of being born LGA. This cannot solely be explained by intrinsic maternal factors as it was also observed in sibling pairs, where the sibling conceived after FET had an increased risk of LGA compared with the sibling born after Fresh embryo transfer.
  
  
  BACKGROUND
  FET singletons have a higher mean birthweight than singletons born after transfer of fresh embryos, and FET singletons may be at an increased risk of being born LGA.
  
  
  METHODS
  The national register-based controlled cohort study involves two populations of FET singletons. The first population (A: total FET cohort) consisted of all FET singletons (n = 896) compared with singletons born after Fresh embryo transfer (Fresh) (n = 9480) and also with that born after natural conception (NC; n = 4510) in Denmark from 1997 to 2006. The second population (B: Sibling FET cohort) included all sibling pairs, where one singleton was born after FET and the consecutive sibling born after Fresh embryo transfer or vice versa from 1994 to 2008 (n = 666). The sibling cohort included n = 550 children with the sibling combination first child Fresh/second child FET and n = 116 children with the combination first child FET/second child Fresh.
  
  
  METHODS
  Main outcome measures were LGA defined as birthweight of >2 SD from the population mean (z-score >2) according to Marsáls curves. Macrosomia was defined as birthweight of >4500 g. Crude and adjusted odds ratios (AORs) of LGA and macrosomia were calculated for FET versus Fresh and versus NC singletons in the total FET cohort. Similarly, AOR was calculated for FET versus Fresh in the sibling cohort. Adjustments were made for maternal age, parity, child sex, year of birth and birth order in the sibling analyses. Meta-analyses were performed by pooling our data with the previously published cohort studies on LGA and macrosomia.
  
  
  RESULTS
  The AORs of LGA (z-score >2) and macrosomia in FET singletons versus singletons conceived after Fresh embryo transfer were 1.34 [95% confidence interval (95% CI) 0.98-1.80] and 1.91 (95% CI 1.40-2.62), respectively. The corresponding risks for FET versus NC singletons were 1.41 (95% CI 1.01-1.98) for LGA and 1.67 (95% CI 1.18-2.37) for macrosomia. The increased risk of LGA and macrosomia in FET singletons was confirmed in the sibling cohort also after adjustment for birth order. Hence, the increased risk of LGA in FET singletons cannot solely be explained by being the second born or by intrinsic maternal factors, but may also partly be related to freezing/thawing procedures per se. In the meta-analysis, the summary effects of LGA and macrosomia in FET versus singletons conceived after Fresh embryo transfer were AOR 1.54 (95% CI 1.31-1.81) and AOR 1.64 (95% CI 1.26-2.12), respectively. The corresponding figures for FET versus NC singletons were for LGA AOR 1.32 (95% CI 1.07-1.61) and macrosomia AOR 1.41 (95% CI 1.11-1.80), respectively.
  
  
  CONCLUSIONS
  Adjustment for body mass index as a possible confounder was not possible. The size of the FET/Fresh sibling cohort was limited; however, the complete sibling cohort was sufficiently powered to explore the risk of LGA. A bias is very unlikely as data coding was based on national registers.
  
  
  CONCLUSIONS
  Our findings are consistent with the previous Nordic studies and thus can be generalized to the Nordic countries. The causes for LGA in FET singletons should be further explored.
  
  
  BACKGROUND
  No external funding was used for this project. None of the authors have any conflict of interest to declare.
authors.affiliation: Department of Obstetrics and Gynaecology, Hvidovre Hospital, University of Copenhagen, Kettegaard Allé 30, Hvidovre DK-2650, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Pinborg
authors.forename: A A
authors.initials: AA
authors.lastname: Henningsen
authors.forename: A
authors.initials: A
authors.lastname: Loft
authors.forename: S S
authors.initials: SS
authors.lastname: Malchau
authors.forename: J
authors.initials: J
authors.lastname: Forman
authors.forename: A Nyboe
authors.initials: AN
authors.lastname: Andersen
mesh_terms: D001724:Birth Weight; D015331:Cohort Studies; D015925:Cryopreservation / Q000379:methods; D003718:Denmark / Q000453:epidemiology; D004624:Embryo Transfer / Q000009:adverse effects / Q000379:methods*; D005260:Female; D005307:Fertilization in Vitro / Q000009:adverse effects*; D005320:Fetal Macrosomia / Q000453:epidemiology / Q000209:etiology*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy
keywords: cryopreserved embryos; frozen embryo transfer; large for gestational age; macrosomia; sibling