ART, birth defects and subfertility—what should prospective patients be told?

To the Editor

We would like to raise some concerns about the methods used to ‘adjust’ for the effect of subfertility in the meta-analysis of ART and major birth defects in the recent paper by Rimm et al. [1] Having also published a systematic review and meta-analysis of ART and birth defects (BDs) [2], we are concerned both by the methods used and some of the statements made in the Rimm et al. paper.

Assumptions underlying the adjustment method:

In their recent meta-analysis, Rimm et al. [1] attempt to ‘adjust’ the study-specific estimates of BD risk for couples conceiving by ART for the proportion they estimate to be due to underlying subfertility, by subtracting the risk for couples who conceived naturally after more than 12 months (based on Zhu et al. [3]). In doing so, they have assumed that the underlying causes of infertility in couples who managed to conceive spontaneously after 12+ months of trying were the same (and of equal severity) as those in couples who required ART to conceive. We think this is unlikely since many couples who proceed to ART treatment, such as those where the female partner has blocked or absent fallopian tubes or is unable to ovulate, or where the male partner has very low or no sperm in his ejaculate, would have little or no chance of conceiving spontaneously.

Meta-analysis is a statistical technique used to summarise the results from many different studies identified through systematic review on the premise that we should look at the body of evidence rather than any study in isolation. Rimm et al. have adjusted the results of the many ART studies they identified (with OR estimates ranging from 0.54 to 15.4) based on an estimate of subfertility derived from a single study, ignoring any of the uncertainty around the single estimate they use. The fact that there are limited data on subfertility and BD risk does not make this valid or appropriate.

Inconsistencies in data presented:

There appear to be errors in some of the adjustments made to the ORs in this meta-analysis.

Although the OR estimates for individual studies are not listed in the original Rimm et al. meta-analysis [4], the ORs presented in the forest plot increase in size from left to right. When these ORs are compared with those in the more recent paper, it is evident that the OR for Place et al. [5] is lower than the one included in the first meta-analysis. Using information in the Place et al. paper, we estimate the OR for major BDs among IVF and ICSI children combined to be 1.36, compared with the OR of 1.24 used in the second Rimm meta-analysis. It is not clear how this was calculated. Moreover, many of the adjusted ORs in Table 1 of the second meta-analysis appear to have been incorrectly calculated (eg MRC, Isaksson, Place, Sutcliffe 1995) so that the hierarchical position of the studies on the second forest plot has changed even further from the original. Some studies also appear to have been incorrectly labelled on the forest plot (eg the OR for Ludwig appears to have been labelled Zadori and vice-versa).

Another inconsistency arises when Rimm et al. make adjustments to studies where the original OR was less than 1. If the argument is that subfertility accounts for some of the cause of BD in couples having ART then you would expect less effect of ART when you account for subfertility—that is the OR estimates should move towards 1. However, in the subset of studies with OR < 1, Rimm et al. have used the adjustment to shift the OR further away from 1, thus increasing the effect of ART and contradicting their own argument.

Exploring subfertility and birth defect risk—what should we be doing?

In the absence of very large (and costly) prospective data sets of women trying to conceive, such as the one used by Zhu et al., where several groups eventually self-identify as their attempts to conceive succeed or fail, we can still explore different aspects of subfertility and BD risk by comparing the prevalence of BDs in the children born to couples in a number of different groups [6]:

1. subfertile patients who have managed to conceive spontaneously while awaiting ART treatment (eg [7]);

2. subfertile patients who have used less invasive non-IVF treatments such as OI, IUI etc. ([3, 8–12]);

3. patients who have undergone ART treatment due to failed vasectomy reversal or tubal ligation reversal but otherwise were essentially fertile (although this group is difficult to identify in sufficient numbers and we are unaware of any published data concerning this subgroup of patients);

4. couples who have conceived both spontaneously and using ART—although again, these couples will no doubt differ in terms of underlying infertility from those who have never managed to conceive spontaneously and could only ever hope to conceive using ART;

5. infertile couples who have used ART; and

6. fertile couples who have not used ART (spontaneous conceptions).

At this stage we have sufficient data to perform a meta-analysis comparing BD risk between groups 5 and 6 but still insufficient data for all the other groups.

Further research examining BD risk in couples with different types of defined infertility is also important to assist with patient counselling, although cause of infertility is often poorly recorded in ART registers and is likely to change with increasing TTP as further tests may be carried out on patients who fail to conceive.

Counselling prospective patients:

A couple seeking ART treatment essentially has two options: use ART and try to have a child, or not use ART and probably not have a child. So for them, the relevant piece of information is not the BD risk once the effect of subfertility has been removed (if indeed this can be accurately quantified), but the overall risk of having a child with a BD if they use ART. We urge caution when communicating risks associated with ART treatment to prospective patients. All counselling should be based on the best available evidence; to date, that evidence suggests that an increased risk of major BDs exists in children born after ART (in the order of 30–40%).[2] Couples should also be told that an increased BD risk also appears to exist, and is biologically plausible, in subfertile patients who manage to conceive spontaneously.