Assisted Reproduction and Neonatology

Assisted Reproductive Technologies have a number of impacts on Neonatology.

By far the most important is the increased risk of prematurity due to multiple gestation. In the USA and Canada (outside of Quebec) the frequency of multiple gestation among IVF pregnancies is about 30%. Pregnancies with more than one baby are much more likely to deliver before term, and the relative increase in extreme prematurity (before 28 weeks) is even more marked.

This is almost entirely due to the transfer of multiple embryos. (There is a slight increase in embryos splitting in two and creating monozygotic twins after embryo transfer, leading to a few identical twins being born.) So the increase in twins is almost completely avoidable. Why do fertility doctors continue to transfer multiple embryos when the risks are so clear? A common response is that women want to have twins. Even after counselling about the substantial increase in risks, women will often request to have (at least) 2 embryos transferred. The image of twins in the public eye is almost universally positive: many celebrities having IVF have had twins, and the cute magazine pictures never mention the increased maternal and fetal/neonatal risks. Women having IVF also have to go through egg retrieval, travel to fertility clinics, time off work, and major costs; all of which increase the attractiveness of having twins.

However, fertility doctors do not have an obligation to increase their patients’ risks, even if those patients request it. They certainly do not have an obligation to increase the risks to the future children of their patients. But the pressures to transfer multiple embryos are substantial; so even though the Canadian fertility society ‘recommends’ single embryo transfer, this is only done less than 5% of the time when there is a choice (I mean when there is more than 1 viable embryo and they decide to transfer only 1 of them, what is known as ‘elective single embryo transfer’). Why is it so rare? Probably because the fertility doctors themselves down-play the risks; after all, most of the time the pregnancy will at least get close to term and the moms and babies will usually come out of it OK. Probably also because there is a risk that the woman will just go elsewhere if they don’t comply and transfer 2 embryos. Probably also because the pregnancy success rates will go down (in fact this is a minor effect, in women under 35 the success rates are just about identical for single and double embryo transfers) and they worry that the advertisements on their web sites will have to be changed, and they will lose business as a result.

We need legislation. Elective single embryo transfer should be enforced. Unfortunately, if this was done by itself it is likely that women will travel somewhere else to have multiple embryos transferred. So infertility should be recognized as a health problem, and treatments covered by insurance programs, and by public health systems. In fact some treatments are already covered: tubal surgery to re-open blocked fallopian tubes is reimbursed (everywhere, as far as I know); the problem is that it doesn’t have a high success rate, nowhere near as high as IVF.

If IVF was regulated, and paid for, then fertility clinics could perform elective single embryo transfer, without the fear that women would go elsewhere for their treatments. This has happened in Québec.

Since the new government program was introduced, which pays for IVF (under certain conditions) and requires elective single embryo transfer (with a small number of exceptions) the twin frequency has dropped from 30% to less than 5%. The savings in neonatal intensive care costs from having fewer preterm twins will pay for this program.  (Janvier A, Spelke B, Barrington KJ. The epidemic of multiple gestations and neonatal intensive care unit use: the cost of irresponsibility. J Pediatr. 2011;159(3):409-13. ) As well as having major benefits in human terms. The same effect has been seen elsewhere, in Sweden for example.

Advances in the techniques used can also reduce the other adverse consequences of single embryo transfer, for example eggs retrieved can be frozen, and used for a second pregnancy with good success rates;, which means that the unpleasant procedures involved in egg retrieval only have to be suffered once.

But doesn’t all this messing about with human eggs, sperm, and embryos affect the way they develop? (Finally getting to the new publication which stimulated this post) A paper in the New England Journal of Medicine, from an analysis of linked Australian databases, shows no increase in congenital anomalies after most IVF, when other risk factors are adjusted for.  Davies MJ, Moore VM, Willson KJ, Van Essen P, Priest K, Scott H, et al. Reproductive technologies and the risk of birth defects. N Engl J Med. 2012;366(19):1803-13

Women having babies after IVF were older, and with different socio-economic status, ethnic background, and so on. Even though there was an increase in congenital anomalies after IVF this difference disappeared after adjusting for these differences in maternal characteristics. This is consistent with other studies, and a previous meta-analysis. As others have also shown, though, the specific procedure called ICSI (intra-cytoplasmic sperm injection) did increase congenital anomalies, even after correcting for maternal characteristics.  Babies born after ICSI had about a 50 to 60% increase in the risk of congenital anomalies.

They also showed a substantially increased Odds for having cerebral palsy: almost 3 times as many infants born after IVF had cerebral palsy compared to the spontaneously conceived children.

This paper also confirms what I said above, pregnancies from IVF with twins are much more likely to deliver extremely early than spontaneous pregnancies with twins. 14% of the IVF twins delivered before 32 weeks, compared to 9% of the spontaneous twins. This was even true among the singletons (2% before 32 weeks compared to less than 1%). This may be partly responsible for the increase in cerebral palsy with IVF, which is more common among premature babies.

You may notice though, if you read the paper, that the frequency of cerebral palsy among IVF twins was not significantly increased compared to spontaneous twins. You may also notice that the frequency of cerebral palsy among spontaneous twins was about 5 times higher than among spontaneous singletons. This phenomenon is largely due to something which is already known, there is a major increase in cerebral palsy among identical twins, which are quite unusual after IVF.

The take home message of the paper: IVF does not increase congenital anomalies unless ICSI is involved. And do NOT transfer more than 1 embryo!

About Keith Barrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
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