title: Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta-analysis.
abstract: BACKGROUND
  Assisted reproduction technology (ART) is used worldwide, at increasing rates, and data show that some adverse outcomes occur more frequently than following spontaneous conception (SC). Possible explanatory factors for the well-known adverse perinatal outcome in ART singletons were evaluated.
  
  
  METHODS
  PubMed and Cochrane databases from 1982 to 2012 were searched. Studies using donor or frozen oocytes were excluded, as well as those with no control group or including <100 children. The main outcome measure was preterm birth (PTB defined as delivery <37 weeks of gestation), and a random effects model was used for meta-analyses of PTB. Other outcomes were very PTB, low-birthweight (LBW), very LBW, small for gestational age and perinatal mortality.
  
  
  RESULTS
  The search returned 1255 articles and 65 of these met the inclusion criteria. The following were identified as predictors for PTB in singletons: SC in couples with time to pregnancy (TTP) > 1 year versus SC singletons in couples with TTP ≤ 1 year [adjusted odds ratio (AOR) 1.35, 95% confidence interval (CI) 1.22, 1.50]; IVF/ICSI versus SC singletons from subfertile couples (TTP > 1 year; AOR 1.55, 95% CI 1.30, 1.85); conception after ovulation induction and/or intrauterine insemination versus SC singletons where TTP ≤ 1 year (AOR 1.45, 95% CI 1.21, 1.74); IVF/ICSI singletons versus their non-ART singleton siblings (AOR 1.27, 95% CI 1.08, 1.49). The risk of PTB in singletons with a 'vanishing co-twin' versus from a single gestation was AOR of 1.73 (95% CI 1.54, 1.94) in the narrative data. ICSI versus IVF (AOR 0.80, 95% CI 0.69-0.93), and frozen embryo transfer versus fresh embryo transfer (AOR 0.85, 95% CI 0.76, 0.94) were associated with a lower risk of PTB.
  
  
  CONCLUSIONS
  Subfertility is a major risk factor for adverse perinatal outcome in ART singletons, however, even in the same mother an ART singleton has a poorer outcome than the non-ART sibling; hence, factors related to the hormone stimulation and/or IVF methods per se also may play a part. Further research is required into mechanisms of epigenetic modification in human embryos and the effects of cryopreservation on this, whether milder ovarian stimulation regimens can improve embryo quality and endometrial conditions, and whether longer culture times for embryos has a negative influence on the perinatal outcome.
authors.affiliation: Fertility Clinic, Section 4071, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9, DK - 2100 Copenhagen, Denmark. pinborg@nru.dk
authors.forename: A
authors.initials: A
authors.lastname: Pinborg
authors.forename: U B
authors.initials: UB
authors.lastname: Wennerholm
authors.forename: L B
authors.initials: LB
authors.lastname: Romundstad
authors.forename: A
authors.initials: A
authors.lastname: Loft
authors.forename: K
authors.initials: K
authors.lastname: Aittomaki
authors.forename: V
authors.initials: V
authors.lastname: Söderström-Anttila
authors.forename: K G
authors.initials: KG
authors.lastname: Nygren
authors.forename: J
authors.initials: J
authors.lastname: Hazekamp
authors.forename: C
authors.initials: C
authors.lastname: Bergh
mesh_terms: D015925:Cryopreservation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D019102:Infant, Very Low Birth Weight; D007246:Infertility / Q000453:epidemiology*; D011247:Pregnancy; D047928:Premature Birth / Q000453:epidemiology* / Q000235:genetics; D027724:Reproductive Techniques, Assisted / Q000009:adverse effects*