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Lightening the burden of care in assisted reproductive technology

      In our March 2016 Views and Reviews section, we discussed the large amount of data indicating that psychological stress reduces in vitro fertilization (IVF) success (
      • Meldrum D.R.
      • Casper R.F.
      • Diez-Juan A.
      • Simon C.
      • Domar A.D.
      • Frydman T.
      Aging and the environment affect gamete and embryo potential: can we intervene?.
      ). We referred to a landmark study showing that increased diastolic blood pressure was highly predictive of poor IVF outcomes. I can identify with those findings. My diastolic pressure was over 90 during my internship and is now under 70. When my IVF program was first housed in the university, a patient would come back to my office completely unglued because the pharmacy had run out of gonadotropins. I have no doubt that moving to a setting where all parts of IVF could be smoothly applied contributed to our early good success. All programs should be aware that the entire team from the front desk to billing contributes to positive outcomes.
      We also referred to the increasing emphasis on the burden of care throughout medicine. For example, in assisted reproductive technology (ART), much has been made of the shorter treatment and reduced number of injections with antagonist protocols. However, as we embrace further refinements in the practice of ART, I will argue, illustrated by specific examples, that reducing the burden of care must be evaluated much more comprehensively to include psychological stress and the entire treatment from patient preparation through to successful birth, and even early child care. We must assume adding stress impacts outcomes. Cumulative stress undoubtedly leads some couples to drop out of further treatment. Remarkably, couples sometimes even dissolve their relationship after being successful.
      Before treatment, an increasingly common routine has been to recommend a panel of genetic screening tests far exceeding the limited number recommended by various organizations overseeing our specialty. The potential benefit is undeniable, although small, but how much stress does it add? When the female partner is informed she has a genetic abnormality, her male partner is tested. If they both carry the abnormal gene they then have genetic counselling, including issues as to whether their other children, their sibs, and their ART offspring should be tested. Are we causing more harm than benefit when ART success is of overriding importance to the couple?
      Preimplantation genetic screening (PGS) on trophectoderm biopsies has markedly reduced miscarriage in older women, which should decrease cumulative stress and drop-outs from treatment. However, as the sophistication of PGS platforms has evolved to NextGen sequencing it has become possible to define a larger group of intermediate reads as “at risk for mosaicism” (reviewed in this issue). Does such refinement increase the psychological burden of care? Instead of the couple receiving a report indicating which embryos are euploid or aneuploid with a very small number designated as mosaic (and understanding that there is a small error in any of those determinations), couples can be faced with up to 30% of their embryos being designated as possibly abnormal (depending on the bioinformatics used by the particular laboratory). That may result in deselection of a euploid embryo for transfer that has superior morphology, or with a couple preferring to think in black and white, to even discarding such an embryo. Genetic counselling may indicate there have been no abnormal births reported with that particular chromosome/s being mosaic, but the nature of mosaicism in potentially involving other tissues maintains a level of uncertainty. Again, might that result in causing more harm than benefit by increasing the cumulative psychological burden of care? From very early reports it appears that reducing the ranking of those embryos further reduces miscarriage and that transfer of those embryos is associated with reduced implantation, although some of those embryos would have been called aneuploid using other platforms or bioinformatics and therefore excluded from transfer. On the other hand, decreasing the rank of a superior morphology embryo may delay success or its value could be entirely lost if the couple elects not to use it. There is also a real question as to the outcome of any ongoing pregnancies resulting from those “at risk” embryos. In one report 6 normal infants were born after transfer of mosaic embryos analyzed by array comparative genomic hybridization, which requires a higher level of mosaicism for detection (
      • Greco E.
      • Minasi M.G.
      • Fiorentino F.
      Healthy babies after intrauterine transfer of mosaic aneuploid blastocysts.
      ). In another study of chorion villus biopsy of 399 IVF pregnancies at 10 to 13 gestational weeks, the incidence of mosaicism, confirmed by karyotype (and rarely found in fetal cells), was 1%–2% and not significantly different from infertile couples not having IVF or having spontaneous pregnancies (
      • Huang A.
      • Adusumalli J.
      • Patel S.
      • Liem J.
      • Williams 3rd, J.
      • Pisarska M.D.
      Prevalence of chromosomal mosaicism in pregnancies from couples with infertility.
      ). In both reports the authors speculated that normal cells preferentially divide, progressively leaving the abnormal cells behind and primarily confined to the placenta (
      • Huang A.
      • Adusumalli J.
      • Patel S.
      • Liem J.
      • Williams 3rd, J.
      • Pisarska M.D.
      Prevalence of chromosomal mosaicism in pregnancies from couples with infertility.
      ). When any new test is devised, its use by clinicians should await sufficient data on sensitivity and specificity and analysis of all outcomes (benefit and harm), including births, and in this case, specific to the particular bioinformatics being utilized to define the “at risk” embryos.
      My final example of an extremely stressful part of IVF is multiple pregnancies. With twins, the incidence of divorce is significantly increased. For every total failure of a couple's relationship we can imagine the additional number of relationships stressed almost to the breaking point. Twin pregnancies are associated with a 5-fold increase of preterm delivery, a doubling of gestational diabetes and preeclampsia, 6-fold increases of perinatal mortality and cerebral palsy, increases of a variety of neuro-developmental and behavioral disorders, and a lot of missed sleep and organizational and financial issues. Even earlier delivery at term has been correlated with decreased academic achievement (
      • Noble K.G.
      • Fifer W.P.
      • Rauh V.A.
      • Nomura Y.
      • Andrews H.F.
      Academic achievement varies with gestational age among children born at term.
      ). Having twins hugely increases the total burden of care of IVF and in my view is not “OK” (some practitioners have even promoted the value of twins to their IVF couples!). It is therefore unfortunate that the Society for Assisted Reproduction Technology (SART) (most likely due to distractions related to the numerous issues requiring attention in devising the newest SART clinic reporting system) seems to have put their quest to reduce twinning on the back burner. Rather than having the average number of embryos transferred, the percentage of elective single embryo transfers (eSET), and the implantation rate displayed at the very top, all the user first sees without drilling deeper is the birth rate per cycle and the percentages of singleton deliveries and multiple pregnancies. Without being a sophisticated and informed individual, a program performing a high percentage of eSET will not be recognized for their efforts to reduce this important contributor to morbidity, mortality, and cumulative burden of care, and will even be penalized because of rampant use of the SART report to choose “the best” provider. SART is inadvertently encouraging rather than discouraging double embryo transfer and I hope that can be remedied.
      The issues discussed above are of even greater importance because cumulative burden of care will influence drop-out, which has the same result for those couples as being unsuccessful with treatment. Fortunately the option of PGS reduces miscarriage and futile transfers, the number 1 and 2 causes of severe stress contributing to drop-out (
      • Hammarberg K.
      • Astbury J.
      • Baker H.
      Women's experience of IVF: a follow-up study.
      ), but cumulative burden of care undoubtedly brings many couples to that breaking point.
      We are naturally exuberant about refinements in our ART care, but adoption of any refinement should obligate a program to carefully consider its impact on overall burden of care before making a decision. Just as the U.S. government requires an Environmental Impact Statement for new projects potentially influencing our surroundings, the complex and delicate system of IVF should receive an equivalent degree of vigilance.

      References

        • Meldrum D.R.
        • Casper R.F.
        • Diez-Juan A.
        • Simon C.
        • Domar A.D.
        • Frydman T.
        Aging and the environment affect gamete and embryo potential: can we intervene?.
        Fertil Steril. 2016; 105: 548-559
        • Greco E.
        • Minasi M.G.
        • Fiorentino F.
        Healthy babies after intrauterine transfer of mosaic aneuploid blastocysts.
        N Engl J Med. 2015; 373: 2089-2090
        • Huang A.
        • Adusumalli J.
        • Patel S.
        • Liem J.
        • Williams 3rd, J.
        • Pisarska M.D.
        Prevalence of chromosomal mosaicism in pregnancies from couples with infertility.
        Fertil Steril. 2009; 91: 2355-2360
        • Noble K.G.
        • Fifer W.P.
        • Rauh V.A.
        • Nomura Y.
        • Andrews H.F.
        Academic achievement varies with gestational age among children born at term.
        Pediatr. 2012; 130: e257-e264
        • Hammarberg K.
        • Astbury J.
        • Baker H.
        Women's experience of IVF: a follow-up study.
        Hum Reprod. 2001; 16: 374-383