Cerebral palsy after IVF studied

The Daily Telegraph has reported that “IVF could double the risk of cerebral palsy”. The newspaper also said “IVF itself could increase the risk rather than it being a consequence of the parents’ impaired fertility”.

The news is based on Danish research that looked for possible links between time taken to conceive, the use of IVF and the risk of cerebral palsy. The results showed the risk of cerebral palsy bore no relation to the length of time taken to conceive but that there was approximately a two-fold increase in the risk of cerebral palsy in children born following IVF. However, when the researchers excluded twin and triplets and only looked at single births there was no increased risk associated with IVF.

In the UK, the number of embryos transferred to the mother after IVF is limited to avoid multiple pregnancies and their associated risks. Also, this research did not look at the underlying causes or severity of infertility in the participants that it studied. It is too early to say whether there is an increased risk of cerebral palsy with IVF. More studies are needed to understand the potential risk levels associated with multiple embryo transfers.

Where did the story come from?

The study was carried out by researchers from The University of Aarhus, Denmark. It received funding from The Danish Medical Research Council and the US National Institutes of Health. The study was published in the peer-reviewed medical journal, Human Reproduction.

This research was generally covered well by The Daily Telegraph and BBC News, which both pointed out that the absolute risk of cerebral palsy is low. The BBC’s report included some background information on IVF and cerebral palsy, explaining some studies have suggested that twin pregnancies may have an influence on the risk of cerebral palsy.

The BBC article also quoted one of the study authors, who said that the extra risk of IVF ‘may have disappeared’ in countries that transferred only a single embryo, highlighting that different countries may have differing IVF regulations and practices.

What kind of research was this?

This cohort study followed pregnant women from 16 weeks of pregnancy to the birth of their baby. It looked at the risk of cerebral palsy and whether it was associated with the parents’ fertility history, i.e. was the risk greater for babies of parents who took longer to conceive or had IVF treatment.

The researchers were interested in this as some studies had already shown that children born after in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) have a higher risk of cerebral palsy. One study had shown that the association between IVF and cerebral palsy disappeared after the data was adjusted for the years of delayed conception that the couples had experienced.

Another study had reported a higher risk of cerebral palsy among spontaneously conceived children of sub-fertile couples (those with a decreased chance of getting pregnant) who had been registered for treatment at an IVF clinic but had not yet received treatment.

The researchers wanted to look at a large cohort of families who had either had conceived promptly after trying for a baby, had taken longer to conceive or who had IVF treatments, in order to see whether the risk of cerebral palsy was indeed associated with some aspects of parental fertility.

What did the research involve?

The research used data from women included in the Danish National Birth cohort whose pregnancy resulted in a live birth between 1997 and 2003.

The women were interviewed while they were pregnant and asked whether the pregnancy was planned and, if so, how long they had tried to become pregnant before succeeding. The women who reported trying for over six months were asked whether they or their male partner had received any infertility treatment, including ICSI, IVF intrauterine insemination (IUI) or ovulation induction (OI). The data was validated through a Danish IVF register.

The births were grouped into seven categories:

time until pregnancy of 0-2 months (reference group)
time until pregnancy of 3-5 months
time until pregnancy of 6-12 months
time until pregnancy of over 12 months
born after IVF or ICSI
born after ovulation induction with intrauterine insemination
born after ovulation induction without intrauterine insemination

Cases of cerebral palsy were identified by linking the details of the babies to the Danish Cerebral Palsy Register, which includes all children with a diagnosis of cerebral palsy validated by a neuro-pediatrician in Denmark since 1995. There are approximately 170 new cases of cerebral palsy in Denmark every year.

The researchers used a statistical technique called Cox regression to assess whether there was a link between time until pregnancy was achieved and the risk of cerebral palsy. They also looked at the potential influence of maternal age, smoking during pregnancy, education of the mother, whether the child was male or female and the number of previous births the mother had.

The researchers also looked at whether multiple pregnancies and pre-term births (before 37 weeks of gestation) affected any association. They adjusted for factors such as age, smoking, education, sex of child and preterm birth.

The IVF register did not feature any mothers younger than 20 years of age and the researchers excluded 519 children born to mothers under 20 years of age.

What were the basic results?

Among the 90,203 children born, 165 were diagnosed with cerebral palsy (0.18%). Of these, 145 children had been among the 86,223 singleton births (0.17%), 18 were one of the 3,834 twins born (0.47%) and two were one of the 95 triplets born (2.11%).

The researchers found that there was no association between the time attempting to conceive and the risk of cerebral palsy.

A total of 35,848 children had been born within 0-2 months of their parents planning for a pregnancy, 3,000 of whom were born following IVF or ICSI. The researchers found that after all adjustments babies born to parents who had IVF or ICSI had a 2.3 times greater risk of cerebral palsy than babies conceived straight after trying (within 0-2 months). The hazard ratio [HR] was 2.30, 95% and the confidence interval [CI] was 1.12 to 4.73].

There were no differences in the type and severity of cerebral palsy seen in those children born after fertility treatment and those born without fertility treatment.

The researchers repeated the analysis using data from just singleton pregnancies. There were 33,409 singleton children born within 0-2 months of planning pregnancy and 43 of these children (0.13%) had cerebral palsy. Some 1496 IVF or ICSI treatments resulted in singleton pregnancies and of these, five children (0.33%) were born with cerebral palsy. The adjusted HR was 2.55, 95%; CI 0.95 to 6.86, meaning that there was no statistically significant difference in the risk of cerebral palsy in singleton pregnancies resulting from IVF or ICSI compared to spontaneous pregnancies.

How did the researchers interpret the results?

The researchers said that in a large cohort of prospectively followed children there was “no significant association between time to pregnancy and the risk of cerebral palsy in children conceived spontaneously, whereas children born after IVF or ICSI had an increased risk of cerebral palsy.”

Conclusion

This large cohort study looked at whether there was an association between time needed to conceive, the use of IVF and ICSI and the risk of cerebral palsy.

The researchers adjusted the data to take into account other factors (such as age) that are known to be associated with cerebral palsy, which adds strength to the study. The incidence rates of cerebral palsy in Denmark were low (around 0.18% of births) and although the researchers found there was an increased association between IVF and ICSI and cerebral palsy, there are a few limitations to this study that the researchers highlight.

The research did not address the severity or cause of infertility that had led couples to require IVF. In this research all attempts to get pregnant that took over 12 months were analysed as a single group but parents requiring IVF may had tried for substantially longer than one year to have a child before having IVF. Therefore, the measures of time trying to conceive may not accurately reflect the severity or nature of infertility experienced.
When the researchers only included singleton pregnancies, there was no difference between IVF and spontaneous births in terms of the risk of cerebral palsy.
This research was carried out in Denmark but different countries may have different IVF regulations, which may in turn affect the chances of having multiple births through IVF. In the UK, women under 40 can have one or two embryos transferred into the womb. In women over 40 years, a maximum of three can be transferred. The number transferred is restricted owing to the risks associated with multiple births.
The absolute proportion of children who had cerebral palsy was low. Although there was a large cohort of mothers who had normal pregnancies (over 30,000), there were 3,000 women who had IVF treatment. Therefore, our confidence in the estimates should reflect the relatively smaller numbers of patients involved and the wide confidence intervals featured in the results.

This study shows that IVF and ICSI may be associated with a small increased risk of cerebral palsy but further research is needed to assess whether this may be due to aspects of the technique itself, multiple transfers or other factors associated with fertility that may influence pregnancy.