Reproductive technologies: the alchemy of life

There have been few advances that surpass the treatment of infertility for the combination of extraordinary technical prowess, transformative experience for patients, and ethical debate in the community.

Innovation operates at the edge of knowledge, and how far one reaches beyond the current boundary depends on the balance of risks and rewards. With regard to assisted conception, the rewards are great and the rate of innovation extraordinary. There are now around 4 million individuals on the planet who were born as a result of assisted conception — enough to populate their own country.2 While wishing to support couples in their desire for parenthood, we need to be mindful of the health and welfare implications for the growing global population.

Evaluating the negative outcomes of fertility treatment is difficult because of the complex range of treatment options that may be used in combination and the time lag between birth and the final outcomes. A starting point would be to develop robust indicators that can be assessed early in life. Accordingly, we have recently published research that helps clarify the risk of birth defects associated with assisted reproductive technology.3 We found that birth defects were associated with both parental infertility and with factors of infertility treatment.

We studied nearly 310 000 South Australian births, including more than 6100 births after assisted conception, in the years 1986 to 2002. The children were followed up until their fifth birthday to make sure that all birth defects were recorded. We were able to adjust for parental factors recognised as being associated with birth defects, including maternal age, parity, maternal body mass index, pre-existing diseases and conditions during pregnancy, and parental occupation.

In our study, unassisted conceptions were associated with a 5.8% chance of a birth defect, while assisted conceptions were associated with an 8.3% chance. The difference is small in absolute terms, yet each of the excess defects is, in principle, avoidable, and some are associated with major disability and very high lifetime costs.

Previous studies have also shown that assisted conception is linked to an increased risk of birth defects.4-7 A 2005 systematic review offers the highest level of evidence for observational studies4 and can be interpreted as demonstrating that the link between infertility treatment and birth defects is likely to be causal.

Our study was not large enough to assess the risks for individual birth defects, so they were analysed in groups. Increased risks were found for cardiovascular defects, musculoskeletal defects, urogenital defects, gastrointestinal defects, multiple defects in the same child, and cerebral palsy. These broad categories are consistent with results observed in a number of studies, which suggests similar aetiological factors are involved.

We did have sufficient power to tease out the risks associated with different types of assisted conception. After adjusting for patient factors, in-vitro fertilisation (IVF) did not show an increased rate of birth defects compared with spontaneous pregnancies, and the chance of having a baby with a birth defect was 32% less with IVF than after intracytoplasmic sperm injection (ICSI).

It is broadly acknowledged that severe semen defects may increase the risk of defects in offspring. It is less clear whether ICSI per se increases the risk, although ICSI does have a number of features that make this plausible,8 including that direct sperm injection into the ovum may overcome biological barriers that would normally prevent fertilisation from occurring, such as using immotile sperm. Accordingly, the difference in risk between IVF and ICSI tends to be observed in studies where ICSI was the main approach taken for male-factor infertility, and can be obscured by inclusion criteria when study results are pooled.9

We observed a statistically significant increased chance of birth defects that was particularly evident with ICSI in “fresh” treatment cycles (ie, using only non-frozen embryos). This treatment combination was associated with a birth defect prevalence of 9.9% compared with 5.8% for unassisted conceptions (ie, no fertility treatment). This may be because ovarian stimulation has adverse effects on the intrauterine conditions necessary for embryo implantation, or that freezing and thawing removes vulnerable embryos that have an increased chance of developing into a fetus with a birth defect. However, while we observed that the risk after an ICSI frozen embryo cycle was not statistically significant, because of limited statistical power, we can only conclude that the observed 28% increase in the odds of developing a birth defect compared with spontaneous conceptions may be due to chance, and should not be interpreted as proof of no difference. In contrast to ICSI, our findings affirm the relative safety of single-embryo IVF transfer of embryos after freezing, a practice that has become increasingly important internationally to counter rising multiple pregnancy rates as embryo implantation rates improve.

In a global context, the relative safety of IVF that we observed does not indicate that IVF is invariably performed without risk. For instance, experimental work in cattle and sheep shows that the introduction of human serum into embryo culture media can induce imprinting defects, with outcomes such as “large offspring syndrome”.10 As observed previously by others, the birthweight distribution in both singletons and twins in our study is reduced, which indicates perturbed fetal growth with potential long-term health consequences.

A unique feature of our study was the fact that we could compare babies born to mothers who had a child after assisted conception in addition to a child conceived naturally. These siblings both showed an increased risk of birth defects, suggesting that couples with impaired fertility are at increased risk of having children with birth defects, even without the use of assisted conception. The precise reason for this observation is yet to be determined.

Our study also raises concerns about the level of supervision required when using clomiphene citrate to stimulate ovulation. The drug is widely used internationally and in Australia, with over 37 000 prescriptions approved annually through the Pharmaceutical Benefits Scheme. Our finding of a tripling in the odds for major birth defects after the use of clomiphene citrate is consistent with those of previous studies.11 However, as the number of clomiphene-exposed pregnancies in our study was very small, it is essential that larger and more focused studies are done to clarify the risk with clomiphene exposure and to examine patterns of use.

With regard to future work, we should consider each type of fertility treatment as an exposure in its own right for the purpose of identifying sources of risk and because of variation in clinical practice and patient selection across time and place. Further, we should also consider expanding the range of developmental outcomes that we measure, and develop strategies for studying longer term outcomes, including multigenerational studies.