The Risk of Malformation Following Assisted Reproduction

It is estimated that 10% to 15% of all couples in Europe are childless despite a desire to have children (1). Some of these couples can achieve pregnancy only with the aid of artificial fertilization. Intracytoplasmic sperm injection (ICSI) has been performed in Germany since the early 1990’s: this technique increases the chance that a couple will be able to have a child, particularly if it is the male partner that is infertile. It involves the injection of a single spermatozoon through a needle into the oocyte. Artificial fertilization techniques have been included in the catalog of procedures covered by statutory health insurance in Germany (gesetzliche Krankenversicherung, GKV) since 1990. The German Joint Federal Committee (JFC) has been given the task of writing guidelines regarding the medical details of these techniques in reproductive medicine, including the preconditions for their use and the manner and extent of the interventions to be performed. ICSI was incorporated into the GKV procedures catalog in 2002 (diagram 1). Diagram 1 Treatment options for infertility covered by statutory health insurance in Germany ICSI became the most common method of artificial fertilization shortly after it was introduced; other methods include artificial insemination and in vitro fertilization (IVF). From 2004 onward, couples have been required to pay half of the cost of artificial fertilization themselves. Diagram 2 shows the falloff in case numbers after the 50% co-payment rule was introduced. The introduction of ICSI gave rise to concern that this procedure might cause a higher rate of congenital malformations than in vitro fertilization or spontaneous (natural) conception. There are essentially three factors associated with assisted reproductive methods that might influence the malformation rate: Diagram 2 The number of treatments paid for by statutory health insurance in Germany from 2002 to 2005 including insemination techniques, in vitro fertilization, and intracytoplasmic sperm injection. From 2004 onward, couples were required to pay 50% of the cost ... chromosomal anomalies in the gametes used, medications used to stimulate fertility, and the injection of the sperm cell into the egg cell in ICSI. Injection of a sperm cell into an egg cell circumvents natural selection at the egg cell membrane, damages the egg cell itself, and introduces foreign material (e.g. culture medium) into the cell. There are only a few reports in the literature about the potentially damaging effects of stimulation on mature egg cells; the connection between spermiogram parameters and the occurrence of chromosomal anomalies is better documented (2). In recent years, a number of so-called imprinting defects have been diagnosed in a small number of children conceived by ICSI. Imprinting defects arise through a disturbance of epigenetic processes during gametogenesis and/or the preimplantation phase of the fertilized egg (3). Congenital malformations are inborn structural or functional abnormalities. They can be of mono- or polygenic origin or they may be due to external influences such as teratogenic medications or ionizing radiation. They may also be of multifactorial (genetic and external) origin. In most cases, the cause remains unknown. International classifications distinguish major from minor malformations. There is a problem, however, in that the definitions currently in use are not uniformly applied. A possible solution is provided by the classification system of the European Register of Congenital Anomalies (EUROCAT), in which major malformations are defined as physical abnormalities that are incompatible with life, require surgical correction, and/or cause functional impairment. Such malformations can place major burdens on the affected children and their parents. One-quarter of all deaths in childhood are associated with major congenital malformations (6). In view of these facts, the JFC stipulated, when ICSI was introduced, that the rate of congenital malformations among children conceived by this method should be assessed three years after its introduction. Thus, the question whether children conceived by ICSI have more congenital malformations than those conceived naturally or by IVF was investigated by a systematic evaluation of current data.