title: Risk of major congenital malformations associated with infertility and its treatment by extent of iatrogenic intervention.
abstract: BACKGROUND
  Cumulative evidence from large cohort studies, multicenter studies, and meta-analyses suggests that assisted reproductive technologies are associated with an elevated risk of congenital malformations. Theoretically, there are several putative factors in infertility treatments which may be related to the development of congenital malformations. These include, in part, the exposure to gonadotrophin stimulation and the exposure to supra-physiological levels of E2; the altered physiological environment of implantation; the in-vitro culture conditions at early stages of embryonic development; the artificial selection of sperm for fertilization and the sperm injection process in ICSI and the process of embryo cryopreservation. However, it is also possible that the culprit is not the infertility treatment that leads to the increased risk of congenital malformations but a factor or factors inherent to infertile patients.
  
  
  OBJECTIVE
  The aim of this review is to present the current data, summarize it and define the association between major congenital malformation and different types of infertility treatments as well as to infertility per se.
  
  
  METHODS
  We conducted an extensive search of the medical literature (Pubmed, 1985-2006) to identify all data relating major congenital malformations to infertile couples, infertility treatments or to characteristics of the infertile population. The rates of congenital malformations associated with infertility were analyzed by the degree of iatrogenic intervention to better define the relative risks.
  
  
  RESULTS
  The findings confirmed the increased risk of congenital malformations in relation to in vitro fertilization even in singleton infants. There was no difference in the occurrence of major congenital malformations by either the laboratory maneuvers of sperm or embryos of varying complexity or by the specific medications used for ovarian stimulation or luteal support. Increased risk for congenital malformations was also found in infertile couples in relation to infertility treatment with ovulation induction with or without intrauterine insemination and even in spontaneous conception.
  
  
  CONCLUSIONS
  The data seems to indicate that infertile couples harbor an inherent, a priori risk for congenital malformations in their offspring. The risk increases in direct relation to the severity of infertility treatment in which the pregnancy was obtained. The question still remains if this direct relation reflects the severity of the infertility status of the couple or is related to an added value imposed by the infertility treatment.
authors.affiliation: Infertility and IVF Unit, Helen Schneider Hospital for Women, Rabin Medical Center, Petach Tikva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. j_farni@yahoo.com
authors.forename: Jacob
authors.initials: J
authors.lastname: Farhi
authors.forename: Benjamin
authors.initials: B
authors.lastname: Fisch
mesh_terms: D000013:Congenital Abnormalities / Q000209:etiology*; D005260:Female; D005307:Fertilization in Vitro / Q000009:adverse effects*; D006801:Humans; D007049:Iatrogenic Disease; D007246:Infertility / Q000150:complications / Q000628:therapy*; D008297:Male; D011247:Pregnancy; D011256:Pregnancy Outcome; D027724:Reproductive Techniques, Assisted / Q000009:adverse effects; D012306:Risk; D012307:Risk Factors; D012720:Severity of Illness Index