Risks and complications in assisted reproduction techniques: Report of an ESHRE consensus meeting*

Report prepared by J.A. Land1 and J.L.H. Evers

1 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Academisch Ziekenhuis Maastricht, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands. e-mail: jlan{at}sgyn.azm.nl


    Abstract
 Top
 Abstract
 Introduction
 Background
 Conclusions and recommendations
 References
 
Assisted reproduction technique (ART) is an efficacious treatment in subfertile couples. So far little attention has been paid to the safety of ART, i.e. to its adverse events and complications. The consensus meeting on Risks and Complications in ART held in Maastricht in May 2002 focused on four topics: multiple pregnancies, long-term effects of ART on women, effects of ART on offspring, and morbidity/mortality registries.

Key words: ART complications/ART risks/congenital malformations/elective single embryo transfer/multiple pregnancy


    Introduction
 Top
 Abstract
 Introduction
 Background
 Conclusions and recommendations
 References
 
In Europe more than 200 000 IVF/ICSI cycles are started annually, which account for 500–1500 cycles per million inhabitants per year. In 1998 the clinical pregnancy rate per transfer was 27%, and the total multiple delivery rate was 26% (24% twins). The children born after assisted reproductive techniques (ART) constituted 1–3% of the overall number of live births in European countries (Nygren and Andersen, 2001bGo). These figures indicate that ART is available and practised on a large scale. Numerous scientific studies have shown that ART is an efficacious treatment in subfertile couples. In spite of its established efficacy, little attention has been paid so far to the safety of ART, i.e. to its adverse events and complications.

The European Society of Human Reproduction and Embryology (ESHRE) consensus meeting on risks and complications in ART in Maastricht in May 2002 focused on four topics: multiple pregnancies, long-term effects of ART on women, effects of ART on offspring, and morbidity/mortality registries. It is not the purpose of this report to review the risks and complications of ART. In the text, the only literature that has been included is that on which the conclusions and recommendations of the meeting were based.


    Background
 Top
 Abstract
 Introduction
 Background
 Conclusions and recommendations
 References
 
Multiple pregnancies
If 25% of all pregnancies after IVF/ICSI are twin pregnancies, 40% of all babies born after ART are born as part of a twin pair. Many physicians and patient couples underestimate the negative consequences of twin pregnancies.

Perinatal as well as maternal mortality and morbidity are increased in multiple pregnancies as compared with singleton pregnancies due to a higher rate of prematurity and low birth weights in the children, and due to pregnancy complications in the mothers. Furthermore, parents of multiple births have more stress, and siblings of multiples are more likely to have behaviour problems (Cook et al., 1998Go; Hay et al., 1988Go).

In order to reduce the number of twin pregnancies after ART, elective single embryo transfer (eSET) has been introduced (Vilska et al., 1999Go). The primary aim of eSET is to reduce the multiple pregnancy rate while maintaining an acceptable overall pregnancy rate. The first experiences with eSET in Europe have shown that in selected groups of patients, pregnancy rates after eSET equal pregnancy rates after double embryo transfer (DET) (Gerris et al., 1999Go; Martikainen et al., 2001Go). Patients with good pregnancy potential after eSET, and at high risk for twins after DET, are those who are <=36 years of age, in their first or second ART cycle, and who have at least one good quality embryo. Of these factors, the availability of an embryo with a high potential for implantation is considered the most important. Today, in most centres, embryos are scored according to the number of blastomeres and grade of fragmentation, but it is still under investigation how this grading can be refined and whether additional testing could improve embryo selection.

More randomized studies are needed to make a cost–benefit analysis of eSET versus DET, not only in terms of pregnancy rates and obstetric and neonatal outcome, but also in terms of overall socio-economic cost. Based on these data, recommendations for the number of treatment cycles, and their reimbursement, can be made on a healthcare providers’ level.

Long-term effects of ART on women
Hormonal and reproductive factors are involved in the aetiology of breast cancer and cancers of the female genital tract. Therefore, the effect of fertility drugs on the risk of these cancers has been investigated. Many studies have not been able to reach solid conclusions due to low statistical power, lack of control for important confounders (such as cause of subfertility and parity) and short duration of follow-up.

In a large-scale cohort study in The Netherlands, after a follow-up of 5–8 years, no increased risk of breast and ovarian cancer was found in women who had undergone IVF, as compared with subfertile women who had received no IVF (Klip et al., 2000Go). For endometrial cancer an increased risk was observed in those exposed to IVF as well as in the unexposed group, suggesting a subfertility-related effect which needs further evaluation (Klip et al., 2000Go).

Effects of ART on offspring
Much concern has been expressed about the health of children born after ART. In particular, the risk of boys born to couples with male factor subfertility has drawn attention, since in a substantial number of male factor subfertility cases, a genetic cause can be suspected. These include Y-chromosomal microdeletions, X-chromosomal and autosomal aberrations (i.e. Robertsonian translocations), syndromal disorders featuring infertility (i.e. Kallmann’s syndrome) and ultrastructural sperm defects with a genetic basis (Meschede et al., 2000Go). Theoretically, with ICSI these defects may be transmitted to the following male generation, but it is still too early to draw definitive conclusions.

A significant increase (0.83%) in sex chromosomal aberrations has been reported in pregnancies after ICSI (Bonduelle et al., 1998Go). The results of controlled studies indicate that the risk of congenital malformations after ART is increased as compared with natural conception (5.4 versus 3.8%) (Ericson and Källen, 2001Go). The increased risk of congenital malformations seems to be related to parental characteristics (such as age and parity), and preterm and multiple births. The individual impact of subfertility and of its treatment on the risk of ART children still remains to be elucidated. So far the absolute risk of major congenital anomalies is small, and is not different after IVF and ICSI (3.8 versus 3.4%) (Bonduelle et al., 2002Go).

Morbidity/mortality registration
A European IVF monitoring (EIM) Consortium was established by ESHRE in 1999. Two reports on European ART results have been published, dealing with treatment cycles initiated in 1997 (Nygren and Andersen, 2001aGo) and in 1998 respectively (Nygren and Andersen, 2001bGo). The data collected so far have dealt with availability and efficacy exclusively.

In the near future the EIM Consortium plans to extend the registry in three aspects: to incorporate data on safety (including morbidity and mortality), to provide complete European coverage and to validate the data presented.


    Conclusions and recommendations
 Top
 Abstract
 Introduction
 Background
 Conclusions and recommendations
 References
 
The following conclusions and recommendations were agreed upon during the ESHRE consensus meeting in Maastricht.

Patient selection and counselling for eSET
It was agreed that the essential aim of IVF/ICSI is the birth of one single healthy child, with a twin pregnancy being regarded as a complication. The chances of having a single healthy child after eSET have increased, and equal the spontaneous pregnancy rate in a normally fertile couple.

The consensus recommendations are:
• eSET should be performed if a twin pregnancy is contraindicated and/or if a couple wishes to avoid a twin pregnancy at any cost.

• eSET should be proposed in a first or second IVF/ ICSI cycle in women <=36 years of age if at least one good quality embryo is available.

• Counselling for eSET should be done well in advance of embryo transfer, and in the ART centre the whole staff should be convinced of the importance of avoiding twin pregnancies.

• Spare good quality embryos should be cryopreserved.

Embryo selection for eSET
It was agreed that embryo morphology scoring procedures are insufficiently standardized, and that relevant factors are cell number, lack of fragmentation and multinucleation, and equal cell size.

The consensus recommendations are:
• Each laboratory should have its own reference values based on proven implantation rates.

• Embryos should be checked at x400 magnification at fixed intervals, and any deviations from the normal developmental rate should be recorded.

Counselling patients for long-term effects of ART on women
It was agreed that there is currently no evidence that ART has any effect on the incidence of genital or breast cancer.

Counselling ICSI patients for effects in offspring
According to the current state of knowledge it appears that the incidence of chromosomal abnormalities, including de-novo abnormalities, is higher after IVF and ICSI than in the general population. This may be due to the infertility per se, rather than the ART technique. The incidence of congenital malformations might be higher after IVF and ICSI, but more large prospective studies, with naturally conceived children as controls, are needed to address this question definitively.

The consensus recommendations are:
• Both partners should be fully examined by a gynaecologist and an andrologist. This can be done by one person if qualified in both fields, or by two collaborating specialists.

• Ideally, all couples with severe male subfertility or repeated fertilization failure should be counselled by a genetically trained specialist. In the case of a proven genetic abnormality, a geneticist must be involved.

• Genetic counselling should be offered as a routine part of treatment.

• Laboratory testing should be offered on the basis of clinical investigation. It should include: (i) chromosomal analysis in non-obstructive azoospermia and oligozoospermia with <5x106 sperm/ml; (ii) cystic fibrosis transmembrane regulation (CFTR) gene analysis in congenital bilateral absence of the vas deferens (CBAVD) and related conditions and (iii) Y microdeletion testing in non-obstructive azoospermia and oligozoospermia with <=1x106 sperm/ml.

• In pregnancy, mid-trimester ultrasound screening for congenital malformations and amniocentesis may be considered.

Morbidity/mortality registry
It was agreed that although ART is applied on a large scale in Europe, risks and complications are poorly documented.

The consensus recommendations are:
• Registries should include data on maternal and fetal morbidity and mortality, pregnancy complications, zygosity in twin pregnancies, congenital malformations, multifetal reduction, new procedures (epididymal and testicular sperm retrieval) and non-ART procedures.

• Definitions of terms commonly used in ART should be agreed upon.

• The outcome measure of ART and non-ART should be singleton live birth rate.

Proposed ESHRE activities
ESHRE should support the development of uniform nomenclature for reporting on the outcome and complications of ART. ESHRE should develop guidelines to establish national ART and non-ART registries, and should facilitate collation of data into European registries. Furthermore, standardized patient information materials should be made available for local use. Finally, ESHRE should respond to the need for an embryo morphology workshop.


    FOOTNOTES
 
*A consensus meeting was organized by ESHRE (Maastricht, May 4–5, 2002). The speakers included: E.Bryan (London), C.W.Burger (Rotterdam), M.Camus (Brussels), M.Dhont (Gent), J.Gerris (Antwerp), O.Hovatta (Huddinge), J.A.M.Kremer (Nijmegen), K.Lundin (Gothenburg), E.Nieschlag (Münster), J.G.Nijhuis (Maastricht), K.G.Nygren (Stockholm), C.Staessen (Brussels), E.Van Royen (Antwerp), S.Vilska (Helsinki) and U.B.Wennerholm (Gothenburg).


    References
 Top
 Abstract
 Introduction
 Background
 Conclusions and recommendations
 References
 
Bonduelle, M., Aytoz, A., Van Assche, E., Devroey, P., Liebaers, I. and Van Steirteghem, A. (1998) Incidence of chromosomal aberrations in children born after assisted reproduction through intracytoplasmic sperm injection. Hum. Reprod., 13, 781–782.[Free Full Text]

Bonduelle, M., Liebaers, I., Deketelaere, V., Derde, M.P., Camus, M., Devroey, P. and Van Steirteghem, A. (2002) Neonatal data on a cohort of 2889 infants born after ICSI (1991–1999) and of 2995 infants born after IVF (1983–1999). Hum. Reprod., 17, 671–694.[Abstract/Free Full Text]

Cook, R., Bradley, S. and Golombok, S. (1998) A preliminary study of parental stress and child behaviour in families with twins conceived by in-vitro fertilization. Hum. Reprod., 13, 3244–3246.[Abstract]

Ericson, A. and Källen, B. (2001) Congenital malformations in infants born after in vitro fertilization. A population based study. Hum. Reprod., 16, 504–509.[Abstract/Free Full Text]

Gerris, J., De Neubourg, D., Mangelschots, K., Van Royen, E., Van de Meerssche, M. and Valkenburg, M. (1999) Prevention of twin pregnancy after in-vitro fertilization or intracytoplasmatic sperm injection based on strict embryo criteria: a prospective randomized clinical trial. Hum. Reprod., 14, 2581–2587.[Abstract/Free Full Text]

Hay, D.A., McIndoe, R. and O’Brien, P.J. (1988) The older sibling of twins. Aust. J. Early Child., 13, 25–28.

Klip, H., Burger, C.W., Kenemans, P. and Van Leeuwen, F.E. (2000) Cancer risk associated with subfertility and ovulation induction: a review. Cancer Causes Control, 11, 319–344.[CrossRef][ISI][Medline]

Martikainen, H., Tiitinen, A., Tomas, C., Tapanainen, J., Orava, M., Tuomivaara, L., Vilska, S., Hydén-Granskog, C. and Hovatta, O. and the Finnish ET Study Group (2001) One versus two embryo transfer after IVF and ICSI: a randomized study. Hum. Reprod., 16, 1900–1903.[Abstract/Free Full Text]

Meschede, D., Lemcke, B., Behre, H.M., De Geyer, C., Nieschlag, E. and Horst, J. (2000) Clustering of male infertility in the families of couples treated with intracytoplasmatic sperm injection. Hum. Reprod., 15, 1604–1608.[Abstract/Free Full Text]

Nygren, K.G. and Andersen, A.N. (2001a) Assisted reproductive technology in Europe, 1997. Results generated from European registers by ESHRE. European IVF-Monitoring Programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE). Hum. Reprod., 16, 384–391.[Abstract/Free Full Text]

Nygren, K.G. and Andersen, A.N. (2001b) Assisted reproductive technology in Europe, 1998. Results generated from European registers by ESHRE. European IVF-Monitoring Programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE). Hum. Reprod., 16, 2459–2471.[Abstract/Free Full Text]

Vilska, S., Tiitinen, A., Hydén-Granskog, C. and Hovatta O. (1999) Elective transfer of one embryo results in acceptable pregnancy rates and eliminates the risk of multiple birth. Hum. Reprod., 14, 2392–2395.[Abstract/Free Full Text]