Elsevier

The Lancet

Volume 359, Issue 9305, 9 February 2002, Pages 461-465
The Lancet

Articles
Neurological sequelae in children born after in-vitro fertilisation: a population-based study

https://doi.org/10.1016/S0140-6736(02)07674-2Get rights and content

Summary

Background

There is an absence of population-based longterm studies on the risk of neurological sequelae in children born after in-vitro fertilisation (IVF). Our aim was to compare the frequency of such problems between IVF-born children and controls.

Methods

We did a population-based retrospective cohort study in which we compared development of neurological problems in 5680 children born after IVF, with 11 360 matched controls. For 2060 twins born after IVF, a second set of controls (n=4120), all twins, were selected. We obtained data on neurological problems from the records of the Swedish habilitation centres.

Findings

Children born after IVF are more likely to need habilitation services than controls (odds ratio 1·7, 95% CI 1·3–2·2). For singletons, the risk was 1·4 (1·0–2·1). The most common neurological diagnosis was cerebral palsy, for which children born after IVF had an increased risk of 3·7 (2·0–6·6), and IVF singletons of 2·8 (1·3–5·8). Suspected developmental delay was increased four-fold (1·9–8·3) in children born after IVF. Twins born after IVF did not differ from control twins with respect to risk of neurological sequelae. Low–birthweight and premature infants were more likely to need habilitation than fullterm babies. Maternal age did not affect risk.

Interpretation

Our study suggests that children born after IVF have an increased risk of developing neurological problems, especially cerebral palsy. These risks are largely due to the high frequency of twin pregnancies, low birthweight, and prematurity among babies born after IVF. To limit these risks, we recommend that only one embryo should be transferred during IVF.

Introduction

Infertile couples have had the option of in-vitro fertilisation (IVF) since the end of the 1970s. Today, the technique is used worldwide,1 and 2% of infants born in Sweden are the result of IVF.2 The findings of many studies done on the perinatal and neonatal outcome of infants born after IVF have been reported over the past decade.3, 4, 5, 6, 7 Researchers realise that there is an increase in the frequency of multiple births, preterm births, and in the number of infants born with low birthweights after IVF compared with those born after a natural conception. Nevertheless, according to the results of a study by the Swedish Council on Technology Assessment in Health Care,8 few studies of acceptable size and quality have been done on the long-term outcome of children born after IVF. To study the shortterm and long-term effects of IVF, therefore, a collaborative study between the Swedish Paediatric Association, the Swedish Society for Obstetrics and Gynaecology, and the National Board of Health and Welfare was initiated in 1996. A register of nearly all the children born after IVF pregnancies in Sweden was established, and the perinatal outcome, including the prevalence of malformations, has been published.7

Our aim was to retrospectively assess development of severe neurological sequelae, mental retardation, and severe visual defects in children born after IVF and in population-based controls.

Study participants

We did a population-based retrospective cohort study to ascertain the long-term neurological sequelae of children born after IVF in Sweden between 1982 and 1995. The study was approved by the Swedish Data Inspection Board.

The National Board of Health and Welfare records the details of women, reported to them prospectively by the 14 IVF clinics, which do IVF treatment in Sweden. Those treated with IVF in Sweden but who give birth elsewhere are not included in this register. We used the personal identification number of the women in the register to cross-reference this information with that recorded in the Swedish Medical Birth Registry, to identify children born after IVF and who survived the neonatal period. To ensure an accurate neurological diagnosis, we enrolled only children aged 18 months or older at time of follow-up (1997). We included children born between 1982, when the first Swedish child born after IVF was delivered, and Dec 31, 1995. For every child born after IVF we identified two population-based controls, selected from the Swedish Medical Birth Register, which were stratified for sex, year of birth, and birth hospital. To adjust for the high frequency of twins born after IVF, a further two controls, also twins and matched solely for year of birth, were included in analyses.

Since the 1970s, Sweden has had a nationwide organisation of habilitation centres for children with disabilities, whereby children and adolescents with different neurological impairments, disabilities, and handicaps receive free medical, psychological, social, and educational care in accordance with their individual needs. All 26 childhood disability centres in Sweden participated in our study. People at the habitation centres unaware of whether or not a child was born after IVF searched the records of these centres to ascertain whether each child had received treatment.

Children who attended a habilitation centre had between one and five different neurological diagnoses. A researcher (BS) classified all diagnoses, according to International Classification of Diseases, 10th edition (ICD-10). 138 different diagnoses were reported, and classified into one of 20 groups: mental retardation, infantile autism, behavioural disorders, speech disorders, suspected developmental delay, cerebral palsy, congenital malformations, chromosomal aberrations, neuromuscular disorders, torticollis, brachial plexus injury, disorder of the joints, disorders of the eye, hearing loss, hydrocephalus, habitual tip-toeing, accidents, seizures, other neurological disorders, and other disorders. Thus, all children with mental retardation, independent of severity, were allocated to one group, and all cerebral palsy syndromes were combined. If a child had more than one diagnosis, we registered the one reported by the habilitation centre as the child's major diagnosis. If there was any doubt, cerebral palsy or mental retardation was chosen.

Additionally, we used the nationwide register of blind children and children with severely reduced vision to identify children with severe visual impairment. Reduced vision was defined as visual acuity of 0·3 or less when using both eyes, or severely reduced visual fields (<10°). The register covers all parts of Sweden since the beginning of the 1980s.

We calculated the likelihood of identification of a person on the registers of the childhood disability organisation, or of a person having a specific neurological disease, by use of Mantel-Haenszel odds ratios with test-based confidence limits. We did logistic regression analyses to adjust for potential confounders such as maternal age (<30 or >35 vs 30–35 years), male sex of child, birth year, birth hospital, low birthweight (<2500 g), or low gestational age (<37 weeks). For analyses of severe disorder of vision, we calculated standardised incidence ratios (SIR) compared with expected frequencies in the total population. Results were standardised with respect to year of birth and number of children at delivery. The 95% CIs in these analyses were computed from the Poisson distribution.

The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Section snippets

Results

4353 women had 5680 infants (3228 singletons, 2060 twins, 367 triplets, and 25 quadruplets) after IVF between 1982 and Dec 31, 1995.7 The figure shows the age distribution at follow-up of these children. We identified two controls for each child (n=11 360). To account for the high frequency of twins among the IVF children, we identified a further two controls, also twins, for every IVF-twin. As a result, 83 control children were included in both groups. Thus the total number of controls was

Discussion

In Sweden, concomitant implantation of two embryos during IVF is routine, and results in a pregnancy rate of 30%.2 Almost 50 000 children are now born worldwide every year after IVF, yet the effects of IVF on long-term health of infants are unknown. Numerous studies have dealt with the short-term outcome of IVF—ie, number of pregnancies achieved, multiple pregnancies, infants born, infant mortality, and different malformations.3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 Thus, rates of

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