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The latter half of the twentieth century saw the rapid promulgation of technologies that continue to transform patterns of fertility globally. The introduction of the oral contraception pill in the early 1960s demonstrated an unrivalled capacity to precisely and reliably manage voluntary infertility, transforming the age distribution of female age at first birth and effectively emancipating women to engage with careers and education. In 1978, parallel research in assisted reproductive technology (ART) saw the first birth from in vitro fertilisation which proved the feasibility of effective treatment for involuntary infertility. Following this initial Nobel prize winning breakthrough by Edwards and Steptoe, ART has undergone a rapid transition from laboratory experiment to routine medical care. We are now confronted with the compression of reproductive careers as delayed age at first birth collides with a steep age-related decline in female fertility, with increasing reliance on ART. With approximately 5 million individuals born from ART treatment, we are confronted with a series of questions regarding the effectiveness, safety and long-term social and biological consequences of treatment; both for the recipients of treatment and for the resulting offspring.
Adverse events associated with ART may be attributable to several sources, including patient factors related to infertility, treatment strategies such as multiple embryo transfer, and factors related to specific aspects of treatment such as gamete manipulation or embryo culture media. While ART patients tend to be wealthier and less likely to be smokers, they are on average older with higher body mass, and with a higher prevalence of metabolic disorders such as preexisting diabetes and polycystic ovary syndrome. These latter factors are associated with reduced chance of live birth, increased risk in pregnancy for the mother and increased risk of adverse outcomes for the offspring. Hence, the application of ART in this patient population will contribute to an increased health burden in society and for affected families, which is weighed by each couple undergoing treatment when attempting to reduce the significant handicap of involuntary infertility.1 However, broad generalisations regarding risks and potential benefits are difficult due to the heterogeneity of the patient population with regard to infertility aetiology, which impacts on underlying risk of adverse events and the required type of infertility treatment. Treatment options range from non-invasive ovulation induction through to complex gamete manipulation involving highly invasive procedures for either the woman or man, depending on the infertility aetiology. One of the great challenges for the application of ART will be to partition sources of risk for adverse events, most particularly those that are modifiable. This challenge is all the more difficult when ART is undergoing such rapid and continuous innovation, and the latency to a range of outcomes requires years if not decades of detailed follow-up.
While pregnancy rates from ART historically were in the low single digits, patients with a good prognosis can now achieve cycle-specific pregnancy rates that are substantially higher than spontaneous conceptions in the general population, which are estimated to be around 20%. Double or even triple this rate is now occurring in some patient groups, which may indicate we are witnessing improvements in embryo quality, but also raises questions over the potential consequences for offspring of bypassing selection pressures that constrain spontaneous conceptions.
Pregnancy outcomes after ART treatment are not generally as favourable as for spontaneous conceptions. A substantial proportion of this excess risk is mediated through iatrogenic multiple pregnancy, as multiple embryos are routinely returned to increase the chance of pregnancy. Despite efforts in recent years to quantify the risks associated with this practice, the great cost of treatment means that multiple pregnancy rates often exceed 20%, and that in certain jurisdictions the majority of children born through ART are from multiple gestations, which are viewed as high-risk pregnancies in the general population.
Accordingly, early pregnancy loss, total miscarriage rates and stillbirth rates are elevated compared with the general population. For the mother, there are elevated risks for preeclampsia, gestational diabetes, placenta previa, placental abruption and caesarean delivery.2 Gestations for ART pregnancies tend to be shorter and birthweights of singletons and twins are substantially reduced to a degree that can be comparable to smoking throughout pregnancy. The reasons for this are uncertain, although a range of factors may be involved, including underlying parental disease, and deficiencies in the synthetic culture media and incubation process which cannot yet mimic precisely the complex and varying experience of the rapidly developing embryo as it descends the fallopian tube and enters the uterus prior to implantation.
We are now developing a clearer view of the longer-term implications of ART. Cumulative evidence from a variety of sources including population registries, cohort studies and meta-analyses indicate that ART is associated with an increased risk of major congential malformation, and that this risk appears to vary by treatment modality in addition to patient factors related to infertility.3 The use of embryo freezing appears to substantially reduce the risk, which suggests that the defects are in part intrinsic to the embryos, and that a freeze–thaw cycle adds a selection pressure against developmentally compromised embryos.
Of interest for the future are the more subtle functional characteristics of children as they develop. We are already aware of increased risks for cerebral palsy and increased contact with disability services. Recent work has indicated that under conditions of challenge there is evidence of impaired endothelial function in children, and that linear growth may also be lower than predicted from mid-parental height. It is certainly reasonable to consider a significant investment in the long-term follow-up of ART offspring as they mature and enter their own reproductive careers. This latter aspect is particularly important as the high prevalence of metabolic impairment in the infertile population may have trans-generational effects through direct genetic and more recently identified but as yet poorly understood epigenetic processes related to embryo culture and the potent fertility drugs used in the treatment for ovarian hyperstimulation.4
We also need to consider more complex interactions of ART technology. For instance, we are aware that pregnancies from donor oocytes are at increased risk of preeclampsia, suggesting that there is an immunological difficulty in adapting to the presence of a foreign oocyte. Maternal immune response in pregnancy is also modified by preexisting conditions, such as asthma or atopy; parity, whereby the first pregnancy requires greater immunological adaptation. Extrinsic factors such as medications and smoking also alter maternal immune functioning and methylation, and thereby the conditions under which the fetal immune system develops. The paper by Kallen et al5 demonstrates an association of ART and asthma in offspring. This is an important observation because there are a range of maternal factors that are emerging as modifiers of fetal epigenetic status which may have implications for long-term health of the offspring. That the association could be rendered non-significant after adjusting for years of infertility is pertinent, suggesting a role for maternal immune functioning related to infertility. Of additional interest for future research is the relationship with maternal age and smoking status, which is at variance with spontaneous pregnancies. While smoking in the general population is a risk factor for offspring asthma, it is protective in the ART group, which also suggests an intriguing interactive role with the maternal immune system, as smoking is also protective against preeclampsia, a disease for which women receiving ART treatment are also at increased risk.
It is apparent that we are developing an appreciation of the consequences of ART, and a growing sense of urgency for a greater investment in the continuous monitoring of a rapidly evolving technology. The paper by Kallen et al indicates the complexity and subtlety of emerging questions, and highlights the limitations of our current understanding.
Footnotes
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Contributors MJD planned and wrote this article, and is guarantor for the content.
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Funding Funding for MJD's salary came from Australian Research Council Future Fellowship FT100101018.
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Competing interests None.
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Provenance and peer review Commissioned; externally peer reviewed.
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