title: Increased breast cancer risk in in vitro fertilisation treated women with a multiple pregnancy: a new hypothesis based on historical in vitro fertilisation treatment data.
abstract: BACKGROUND
  Breast cancer risk is temporarily increased after a full-term pregnancy and declines thereafter, possibly due to increased levels of gonadal and placental hormones during pregnancy. Inconsistent results, however, have been reported after twin pregnancies with higher hormone levels. Among women treated with in vitro fertilisation (IVF), for whom the number of embryos available for implantation is known, we recently observed that a multiple birth after implantation of all transferred embryos is associated with higher levels of vascular endothelial growth factor (VEGF). As VEGF is involved in breast cancer progression, we studied the effects of embryo implantation and a multiple birth on breast cancer risk in a nationwide Dutch cohort of IVF-treated women.
  
  
  METHODS
  We performed a cohort analysis among 12,589 women who had been treated with IVF between 1983 and 1995 and completed a risk factor questionnaire between 1997 and 1999. Data on IVF treatment were obtained from medical records. Breast cancer cases were ascertained through linkage with the population-based Netherlands Cancer Registry. Breast cancer risks associated with singleton and multiple births were estimated with Cox regression.
  
  
  RESULTS
  There were 1688 women (13.4%) with multiples, 6027 (47.9%) with singletons and 4874 (38.7%) nulliparous women. Breast cancer occurred in 317 women of whom 57 had multiples. Breast cancer risk was 1.44 times higher in mothers of multiples than in mothers of singletons (95% confidence interval (CI) 1.06-1.97). Risk was highest in women who gave birth to multiples from all embryos transferred (adjusted hazard ratio (HR) 1.86, 95% CI 1.01-3.43), and lower for those with multiples after incomplete embryo implantation (adjusted HR 1.31, 95% CI 0.76-2.25).
  
  
  CONCLUSIONS
  A woman's potential to implant all transferred embryos may be associated with breast cancer risk. Further research is needed to confirm our results and to identify the underlying biological mechanisms.
authors.affiliation: Department of Epidemiology and Biostatistics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: I M
authors.initials: IM
authors.lastname: Krul
authors.affiliation: Department of Obstetrics, Gynaecology and Reproductive Medicine, VU University Medical Centre, De Boelelaan 1117, 1081 HZ Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Groeneveld
authors.affiliation: Department of Epidemiology and Biostatistics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Spaan
authors.affiliation: Department of Epidemiology and Biostatistics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: A W
authors.initials: AW
authors.lastname: van den Belt-Dusebout
authors.affiliation: Department of Epidemiology and Biostatistics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: T M
authors.initials: TM
authors.lastname: Mooij
authors.affiliation: Department of Epidemiology and Biostatistics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Hauptmann
authors.affiliation: Department of Epidemiology and Biostatistics and the EMGO(+) Institute for Health and Care Research, VU University Medical Centre, De Boelelaan 1117, 1081 HZ Amsterdam, The Netherlands.
authors.forename: J W R
authors.initials: JW
authors.lastname: Twisk
authors.affiliation: Department of Obstetrics, Gynaecology and Reproductive Medicine, VU University Medical Centre, De Boelelaan 1117, 1081 HZ Amsterdam, The Netherlands.
authors.forename: M J
authors.initials: MJ
authors.lastname: Lambers
authors.affiliation: Department of Obstetrics, Gynaecology and Reproductive Medicine, VU University Medical Centre, De Boelelaan 1117, 1081 HZ Amsterdam, The Netherlands.
authors.forename: P G A
authors.initials: PG
authors.lastname: Hompes
authors.affiliation: Department of Gynaecology and Obstetrics, Erasmus Medical Centre, Rotterdam, 's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands.
authors.forename: C W
authors.initials: CW
authors.lastname: Burger
authors.affiliation: Department of Obstetrics, Gynaecology and Reproductive Medicine, VU University Medical Centre, De Boelelaan 1117, 1081 HZ Amsterdam, The Netherlands.
authors.forename: C B
authors.initials: CB
authors.lastname: Lambalk
authors.affiliation: Department of Epidemiology and Biostatistics, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Electronic address: f.v.leeuwen@nki.nl.
authors.forename: F E
authors.initials: FE
authors.lastname: van Leeuwen
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000209:etiology*; D015331:Cohort Studies; D005260:Female; D005307:Fertilization in Vitro / Q000009:adverse effects*; D006801:Humans; D015994:Incidence; D011247:Pregnancy; D011272:Pregnancy, Multiple; D012307:Risk Factors; D011795:Surveys and Questionnaires
keywords: Breast cancer; Embryo implantation; IVF; Multiple pregnancy; Nulliparae