Will IVF children be as healthy as spontaneously conceived offspring?

Contrary to widely held beliefs, the history of IVF did not start with the world’s first reported IVF birth in the United Kingdom on  July 25, 1978.3 This birth was, indeed, preceded by years of research and failed attempts by Patrick Steptoe, MD, and Robert Edwards, PhD, who in 1978 finally succeeded, - but also by others. What also is often forgotten is that in those days this kind of research, often, had to take place in relative secrecy because the public, media, and even academia were strongly opposed to such research on medical, ethical, and religious grounds, not only arguing that such research was amoral but also expressing fears that the end products of IVF would be the birth of  “monsters” or, at least, the birth of medically “abnormal” offspring.1 The prominent British magazine Nova in the spring of 1972 ran a story arguing that that, what then were called “test-tube babies,” represented, “the biggest threat (for mankind) since the atom bomb.”4

 

Likely in academic medicine representing this mindset best at the time, was a 1973 incidence at Columbia University, in New York City, where Landrum Brewer Shettles, MD, at the time a prominent faculty member and researcher of the OB/GYN department, who had co-authored the bestseller, “How to Choose the Sex of Your Baby,” which sold over 1 million copies, attempted a first human in vitro fertilization of a woman’s egg with her husband’s semen. His department’s chairman, Raymond L. Vande Wiele, MD, himself at the time a famous infertility specialist, became aware of the experiment and took it upon himself to destroy it. Columbia accused Shettles of “ignoring acknowledged guidelines for human experimentation and acting in unsafe and unethical manner,” and he was forced to leave the institution. Doris and John Del-Zio, the couple that had donated their gametes for the experiment, then sued the university for damages, with the trial that ultimately awarded the couple only $50,000 (they had sued for $1.5 million) , paradoxically, occurring in July of 1978, exactly when the first IVF baby was born five years later.5

 

From experimental procedure to mainstay among fertility treatments

After the first IVF birth, newly established IVF centers, initially, operated under experimental protocols supervised by Institutional Review Boards; but progress was rapid and, within a few short years, IVF went from being an experimental procedure to becoming a mainstay among infertility treatments. This progression was, however, responsibly guided by a research community that, from the very beginning, was concerned about the potential of adverse effects of IVF on offspring. Considerable efforts were, therefore, invested into investigations of newborn follow-ups conceived through IVF, almost uniformly demonstrating no outcome differences between IVF and spontaneously conceived offspring.6-8. When differences were noted, they, usually were explainable by underlying medical and, therefore, dismissed.9

 

A retrospectively very precinct opinion paper on the subject appeared in 2013 penned by the current Editor-in-Chief of Fertility & Sterility, Kurt T. Barnhart, MD, in which he made the point that a preponderance of evidence, indeed, does suggest that IVF is associated with significantly increased perinatal consequences , “even though the vast majority of children conceived with ART are healthy.”10 Following a detailed discussion of methodological limitations of published studies, he concluded that, “the association of IVF with perinatal morbidity does appear to be real,” citing as examples associations between ICSI and certain (urological) congenital abnormalities., of extended embryo culture to blastocyst-stage with preterm delivery, and of more low birth weight after fresh than frozen-thawed embryo transfer all, of course, since further defined.

 

More recently, however, studies started surfacing that suggested that IVF may affect embryos quality and that even a proven healthy uterine environment may not overcome those.11 In other words, the IVF process in itself, may be responsible for increases in adverse perinatal/neonatal outcomes like preterm births, low birth weight, etc., in comparison to spontaneous conceptions. In addition, studies started to appear reporting differences in epigenetic control of transposable elements and imprinted genes in newborns between IVF and spontaneous pregnancies, even in absence of underlying infertility.12 Other observations suggested that embryo culture media affect perinatal pregnancy outcomes.13 Moreover, while maternal diseases in pregnancy have been known to affect pregnancy outcomes for decades, it recently has also become increasingly obvious that maternal disease affects not only can affect pregnancies but can carry over into effects manifesting at adolescent and even adult ages. Good examples are influenza14 and gestational diabetes.15

 

The most recent findings

All of this, of course, raises concerns because the many studies over the decades that, more or less, dismissed concerns about significant adverse effects of the IVF procedure itself on offspring, at least until recently, never looked on potential long-term effects because even the world’s oldest IVF baby is currently only 44 years old. We, simply, have not had in the past, and still do not have, currently, the historical experience that would allow us to predict what the effects of IVF, for example, on longevity may be? Not only can we not predict long-term effects on the first generation of IVF children, but we, of course, can be only even less certain about effects of epigenetic changes induced into embryos during IVF that later may be inherited into future generations.

 

This is why a recent paper in Nature Medicine 2 by Chinese investigators attracted so much attention because they investigated the initial leukocyte telomer length (LTL) of 1,137 individuals from 365 families, including 2002 children conceived by IVF and 205 conceived spontaneously. As a well-known indicator of age-related phenotypes in later life, LTLs offer exactly the kind of  look into the future which we currently do not have regarding the consequences of being born as an IVF baby.

 

The results were concerning: At age one year IVF children had significantly shorter LTLs than spontaneously born children, and this finding was maintained after adjustments for confounding factors. Moreover, the finding was much more pronounced after transfer of blastocyst-stage than cleavage-stage embryos. The association was then further validated in 586 children conceived by IVF from five centers using different LTL quantitation methods and blastocyst-stage transfers in mice postnatally of day-1 and statistically marginally (P=0.042) at six months. Mouse embryos cultured  did not demonstrate suppressed telomer shortened telomer length at late cleavage-stage but did suppress telomerase activity at early blastocyst stage. The authors concluded that, in offspring conceived by IVF, there exists a need to evaluate long-term consequences of IVF on aging-related phenotypes.

 

For IVF practice these findings, however, raise some additional, and more immediate questions regarding almost routine extended embryo culture to blastocyst-stage in most IVF centers: The CHR has, of course, for years in these pages and in many articles in the literature argued against this practice. In here discussed paper’s raised concerns are probably not enough for most IVF centers to curtail current practice patterns to significant degrees, but all IVF practitioners, at minimum, should now more cognizant that there must be a good reason why a patient’s embryos are culture to blastocyst-stage. In other words, a switch in practice patterns from, when in doubt - go with blastocyst-stage culture to, when in doubt go with cleavage-stage embryo transfer, appears now to have much more support.

 

In the same issue of Nature Medicine, Prof. Daniel R. Brison, PhD, FRCPath, a Consultant Clinical Scientist in the British NHS and Scientific Director of a clinical Department of Reproductive Medicine offering infertility treatments, from the University of Manchester at the Manchester Academic Health Sciences Center in Manchester, UK, offers a very well-written brief commentary 16 to the paper by Chinese investigators.2 His concluding paragraph is worth citing verbatim: “Ultimately the aim of such research is not to discourage the use of ART (IVF) but rather to make it as safe as possible. The current ART industry represents a profonde experiment in human reproduction, one that has brought joy to millions of people, but as with any medical intervention, the use of ART also carries risks. Researchers and clinicians owe it to the millions of future children who will be conceived via ART to identify the modifiable risk factors that will optimize their lifelong health, while at the same time caring for extant offspring as they age.” The time appears right to revisit the “extended embryo culture for all “– mantra!

 

REFERENCES

  1. Mulkay M. Scinec, Technology & Human Values 1996;21(2):157-176

  2. Wang et al., Nature Med 2022;28:2646-2653

  3. https://www.history.com/this-day-in-history/worlds-first-test-tube-baby-born#:~:text=On%20July%2025%2C%201978%2C%20Louise,parents%20Lesley%20and%20Peter%20Brown.

  4. https://research.mcdb.ucla.edu/Goldberg/HC70A_W04/pdf/SciAmer:PandoraBaby:2003.pdf

  5. https://www.library-archives.cumc.columbia.edu/obit/landrum-brewer-shettles

  6. Wennerholm et al., Lancet 1998;35(9109):1085-1090

  7. Litzky et al., Epigenetics 2017;12(8):653-661

  8. Halliday et al., Fertil Steril 2014;101(4):1055-1063

  9. Fauser et al., Reprod Biomed Online 2014;28(2):162-182

  10. Barnhart KT. Fertil Steril 2013;99(2):299-302

  11. Woo et al., Fertil Steril 2017;108(6):993-998

  12. Choux et al., Hum Reprod 2018;33(2):331-340

  13. Sacha et al., Fertil Steril 2022;117(6):1246-1254

  14. Song et al., BMC Infect Dis 2020;20(1):502

  15. Hammond et al., Diabetologia 2018;61(5):1037-1045

  16. Brison DR. Nat Med 2022;282476-2477

Author
Norbert Gleicher, MD, FACOG, FACS Norbert Gleicher, MD, FACOG, FACS, is an infertility specialist specializing in autoimmune diseases at the Center for Human Reproduction in the Upper East Side of Manhattan in New York City.

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