New IVF guidance

Behind the Headlines

Monday March 23 2009

Scientists are unclear why more birth defects occur among IVF babies

“Couples having IVF treatment are to be warned for the first time that their children have a higher risk of genetic flaws and health problems,” the Daily Mail reported. The newspaper said that the UK fertility watchdog will warn that children conceived by IVF could be up to 30% more likely to suffer from certain birth defects. It said guidance on IVF will be changed to “warn generally of the risks associated with all types of the procedure”.

This decision by the Human Fertilisation and Embryology Authority (HFEA) is based on a US study published last year. The study found that women who had IVF and ICSI treatment had an increased risk of having a baby with certain birth defects. Although the design of the study means it has some limitations, it provides useful information about the possible increase in the risk of certain defects. The HFEA will publish new advice on assisted reproductive techniques in April.

The 30% increased risk reported by the newspapers is from related research and not directly from this study. What this figure does not communicate is that these birth defects are in fact rare. For example, cleft lip and palate occurs in one in 700 births.

Where did the story come from?

The research was carried out by Dr J. Reefhuis and colleagues involved in the National Birth Defects Prevention Study. The study was funded by the Centres for Disease Control and Prevention. It was published in the peer-reviewed medical journal Human Reproduction.

What kind of scientific study was this?

This case-control study compared mothers of foetuses or live-born infants with a major birth defect with mothers who had live-born infants with no defects. The researchers were particularly interested in the number of birth defects in the offspring of women who had used assisted reproductive techniques (ART). ART included in vitro fertilisation or intracytoplasmic sperm injection (ICSI).

The women were obtained from a larger study, the National Birth Defects Prevention Study, which explored the risk factors for a variety of birth defects. In this study, cases of children with birth defects born between October 1997 and December 31 2003 were identified through the hospital records for 10 states in the US. Children without defects (controls) were drawn from the same population as the cases. The researchers excluded any children who were deemed by a geneticist to have a single-gene condition or a chromosome abnormality, or children whose mothers had type 1 or type 2 diabetes.

All mothers took part in a telephone interview between six weeks and two years after their estimated delivery date. They were asked detailed questions about their use of infertility treatments, particularly the use of ART. Women were considered unexposed to ART if they answered ‘no’ to the question “Did you or the father take any medications or have any procedures to help you become pregnant?”. Women who responded ‘yes’ were questioned further. Any instances where only the father had used infertility treatments, or if the mother had used other types of fertility treatment, were excluded.

In total, 13,586 cases and 5008 controls were interviewed. After excluding cases with missing information, mothers that did not meet the inclusion criteria, and children with rare defects (where there were less than three infants with the defect), there were 9,584 cases and 4,792 controls for analysis.

When analysing the results, the researchers grouped births into singleton and multiple (twins and higher) births. This is because multiple births are strongly associated with both ART and birth defects, i.e. it would be a confounder in the relationship between exposure and outcome. They adjusted their analysis for other possible confounders, including maternal age, study centre, number of previous children, family income and prematurity in the case of septal heart defects (malformation in the wall that separates the left and right sides of the heart).

What were the results of the study?

ART was used by 230 (2.4%) of the case mothers and 51 (1.1%) of control mothers. After adjusting for possible confounding factors, the researchers found that in singleton births, the use of ART increased the likelihood that the child had a septal heart defect (OR 2.1, 95% CI 1.1 to 4.0), a cleft lip with/without cleft palate (OR 2.4, 95% CI 1.2 to 5.1), a blind-ending oesophagus (OR 4.5, 95% CI 1.9 to 10.5) and malformed rectum (OR 3.7, 95% CI 1.5 to 9.1).

There was no increased risk of defects for multiple births.

What interpretations did the researchers draw from these results?

The researchers conclude that some birth defects occur more often among infants conceived with ART. They say that although the reasons behind this are not clear, couples considering ART should be informed of all potential risks and benefits.

What does the NHS Knowledge Service make of this study?

The following should be considered when conclusions are made from this study, particularly about cause and effect:

  • The researchers say that “infants from multiple births were more likely to have major defects”, which seems to be the trend in their analysis. However, their sample sizes were small, and none of these results were statistically significant (i.e. they may have occurred by chance). In this case, the researchers say that “because of the small numbers… it was not possible to reliably assess” the possible effects of ART on the link between multiple gestation and birth defects.
  • The researchers were not able to identify women who had used infertility treatments because they were subfertile (less than normal reproductive capacity). Such women may be at higher risk of having a child with birth defects regardless of whether they used fertility treatments or not.
  • They were not able to verify the gestational age reported by mothers in their interviews, although they say that other studies have shown that women usually give this accurately.
  • One of the main factors that influences the outcome of IVF treatment is maternal age because older women are more likely to have babies with higher rates of birth defects. In their final analyses, the researchers take into account maternal age and only these adjusted results are discussed in this appraisal. The fact that some risks were still significant when accounting for this important confounder strengthens the confidence in the findings.
  • Despite the researchers' efforts to take various possible confounding factors into account, case control studies never completely control for unknown or unmeasured differences between the case and control groups.

It should be pointed out that when the researchers say that women using ART are 30% more likely to have a child with a birth defect, they are using relative measures of risk. Birth defects are actually quite rare, and this figure does not communicate this very well. For example, cleft lip and palate occurs in one in 700 births.

It is unclear where the 30% increase in risk of certain birth defects comes from. A similar figure is quoted by the researchers from other research. This small study has found that certain defects are more common in women who have ART. The extent of the increase in risk will need confirmation in larger population-based studies. Notwithstanding its limitations, the study provides an important direction for future research into how assisted reproduction impacts on the risk of birth defects.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

IVF watchdog to warn of birth defect risks. The Guardian, March 23 2009

New guidance on IVF defects risk. BBC News, March 21 2009

Test-tube baby report will scare parents off IVF. The Independent, March 21 2009

IVF babies in health alert. Daily Mail, March 21 2009

Links to the science

Reefhuis J, Honein MA, Schieve LA, et al. Assisted reproductive technology and major structural birth defects in the United States. Hum Reprod 2009; Advance Access published November 16


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