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National Collaborating Centre for Women's and Children's Health (UK). Fertility: Assessment and Treatment for People with Fertility Problems. London (UK): RCOG Press; 2004 Feb. (NICE Clinical Guidelines, No. 11.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

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Fertility: Assessment and Treatment for People with Fertility Problems.

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17Follow-up of children born as a result of assisted reproduction

17.1. Genetic risks and congenital malformations

The ability of assisted reproduction to circumvent natural barriers to conception has led to concerns about the safety of IVF and ICSI, including their potential to transmit genetic aberrations to the next generation and the long-term consequences on later development of children born as a result of these procedures. Overall, more than one million children in the world have been conceived through IVF since 1978.603 In England and Wales, about 23,000 women were treated and about 8000 babies were born as a result of IVF and/or ICSI in 2000–2001 (about 2500 of these babies were born as a result of ICSI).743 This accounts for about 1.3% of all live births.1126 [Evidence level 3]

To date, there have been no adequate prospective RCTs of sufficient power to assess the efficacy and safety of the various forms of assisted reproduction. Long-term follow-up studies are needed to investigate the safety implications for children born as a result of assisted reproduction.1127 Thus far, follow-up studies have been hampered by the type of surveillance protocol, attrition rate, sample size and lack of standardisation in defining major anomalies. It is also important to recognise that any increased risk may be due to parental factors associated with infertility, which may have led to the use of IVF or ICSI in the first place.1128 [Evidence level 3]

A systematic review1133 of available literature found 30 cohort and case series studies reporting the outcome of ICSI pregnancies on five clinical outcomes (congenital malformations, growth disturbances, neurological development disturbances, chromosomal abnormalities and transmission of subfertility to male offspring).1133 Of the 30 studies included in the review, 13 were rated as acceptable quality cohort studies with well-defined control groups and 17 were cohort or case studies of weaker design. The outcome most reported was congenital malformations. Overall, no increased risk of major birth defects, including chromosomal abnormalities, was found in offspring resulting from treatment of severe male infertility with ICSI compared with offspring conceived by standard IVF treatment or naturally (OR 1.13, 95% CI 1.00 to 1.29, p = 0.06; test for heterogeneity p = 0.35, based on seven cohort studies and two reports). The available data did not indicate an increased risk of any particular malformation, as separate meta-analyses on specific categories of malformations did not show any increased risk after ICSI.1133 [Evidence level 2b–3]

In contrast, a prospective multicentred cohort study carried out in Germany (not included in the systematic review) compared ICSI infants (n = 3372) with normally conceived infants (n = 30,940) and found major malformation in 8.6% of ICSI children versus 6.9% of normally conceived children (crude RR 1.25, 95% CI 1.11 to 1.40).1128 [Evidence level 3]

Whether ICSI treatment of infertile couples with normal karyotypes increases the occurrence of chromosomal abnormalities in offspring is unclear. Sons of infertile males with Y chromosome microdeletions will probably inherit the same abnormality and are therefore likely to be infertile. Males with no known genetic cause for severely compromised sperm quality may also father sons with Y chromosome microdeletions.

A review of seven studies reporting fetal karyotypes analysis (n = 2139) showed that, in comparison with a general neonatal population, there was a slight but significant increase in de novo sex chromosomal aneuploidy (0.6% versus 0.2%) and structural autosomal abnormalities (0.4% versus 0.07%); there was also an increase in the number of inherited structural aberrations (most of which were inherited from infertile fathers).1129 [Evidence level 2b–3]

Attention has focused on reports of imprinting disorders. Several observational studies have reported the occurrence of imprinting defects such as Beckwith–Wiedemann syndrome1130,1131 and Angelman syndrome,1132 in children born after assisted reproduction. The reports on Beckwith–Wiedermann syndrome suggest a six-fold increase in risk against a background prevalence of around 1.3 per 100,000 newborn infants.1130,1131 [Evidence level 3] Further studies are needed to understand the disorders and evaluate their association with assisted reproduction.

ICSI offspring do not seem to have any increase in neurological or psychomotor disabilities compared with offspring conceived by standard IVF treatment. Current data are inconclusive regarding pre- or postnatal growth disturbances. It is not known whether the ICSI method per se, or factors related to the infertile couples, increases the risk of birth and other developmental defects.1133 [Evidence level 2b–3] There is a need for further research on the clinical outcomes of ICSI IVF pregnancies.

17.2. Cancer

A cohort study found that cancer incidence at the age of five years among 2507 children born as a result of assisted reproduction undertaken between 1978 and 1991 did not differ significantly from that in the general population of the UK (2.0 cases observed versus 3.5 cases expected, standardised incidence ratio 57, 95% CI 7 to 206). The mean follow-up time was 8.6 years.1134 [Evidence level 2b] However this analysis lacked statistical power and a larger sample size would be required to detect a difference in the incidence of a rare condition like cancer.

A retrospective cohort study in Sweden found no increase in childhood cancer among 5586 IVF children when compared with babies born in the general population (4.0 cases observed versus 3.6 cases expected). However, this study had limited power to compare cancer incidence.1135 [Evidence level 3]

Another retrospective study in Australia showed no significant increase of cancer in children conceived using IVF and related procedures, compared with a population-based cancer registry (6.0 cases observed versus 4.33 cases expected, standardised incidence ratio 1.39, 95% CI 0.62 to 3.09). The medium follow-up time was three years and nine months.1136 [Evidence level 3]

A cohort study found no increased risk for childhood malignancies between children conceived by IVF or related techniques and children conceived naturally by mothers who were diagnosed with subfertility (16.0 cases observed versus 15.5 cases expected, standardised incidence ratio 1.0, 95% CI 0.6 to 1.7). A direct comparison between IVF children and non-IVF children showed a RR of 0.8 (95% CI 0.3 to 2.3). The average follow-up time was six years.1137 [Evidence level 2b]

A report on childhood cancer from the Netherlands suggested an increased risk of childhood retinoblastoma.1138 [Evidence level 3] This study reported a relative risk in the range 4.9 to 7.2 after assisted reproduction, against a background incidence of 2.6 cases per 100,000 children in the first year of life, and 0.9 per 100,000 in children aged one to four years.

17.3. Psychological and educational development

A case–control study found that developmental indices were positively correlated to gestational age, birth weight and head circumference at birth. Infants conceived by IVF were within the normal ranges of these indices and did not differ from their matched controls.1139 [Evidence level 3]

A cohort study found no significant differences at three years in psychomotor development of children conceived by IVF compared with children born after ovarian stimulation without IVF and children conceived naturally.1140 [Evidence level 2b]

Another cohort study compared families with children conceived through assisted reproduction (including IVF treatment and donor insemination) with families with naturally conceived children.1141 [Evidence level 2b] This study found that the quality of parenting in families with children conceived through assisted reproduction was better than that shown by families with a naturally conceived child. However, no significant differences in children’s emotions, behaviour or relationships with parents were found between the two groups.

A survey of 743 children conceived by IVF over the age of four years showed no significant increase in the rate of behavioural or psychological problems compared with a control group. Neither males nor females from multiple gestation pregnancies had a statistically increased incidence of problems compared with same sex singletons births among the children conceived by IVF or compared with the control group.1142 [Evidence level 3]

RECOMMENDATION

Couples contemplating assisted reproduction should be given up-to-date information about the health of children born as a result of assisted reproduction. Current research is broadly reassuring about the health and welfare of children born as a result of assisted reproduction. [C]

RESEARCH RECOMMENDATION

Long-term longitudinal follow-up of children resulting from assisted reproduction is needed. This research should focus on physical, genetic, psychological and social development, and it should be co-ordinated on a national basis.

Copyright © 2004, National Collaborating Centre for Women’s and Children’s Health.

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Bookshelf ID: NBK45940

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