Please Note: This article does not pertain to genetic testing for serious health conditions like cystic fibrosis or young women with strong ovarian reserve.
PGD is the latest new testing in the IVF market. Not covered by insurance and costing thousands of dollars, does it deliver improved pregnancy rates?
A women comes to my office with 2 failed IVF cycles and several miscarriages. Her diagnosis – older women and poor responder. The doctor suggests PGD/PGS for her next IVF cycle. The doctor believes the embryos have genetic problems leading to miscarriage. The couple pay out of pocket several thousand dollars and have the procedure completed on five embryos. All embryos fail genetic testing and the transfer is cancelled. The couples decides to try another round of IVF. Unfortunately, the cycle only produces four embryos, where the clinic guidelines require five embryos for testing. The couple agree to skip the testing and go to transfer with two embryos and freeze two. The client becomes pregnant and has a healthy girl. Two years later the client transfers the last two embryos and has another girl.
This was my first exposure to the mixed results of PGS/PGD testing. I have been questioning PGS testing ever since.
I could kick myself now……I read (and threw out) a wonderful research article in Fertility and Sterility about mice embryos purposely damaged and transferred back to the mother mouse. Of the baby mice bourn to the mother mouse, all were healthy. The authors speculated the female mouse’s uterine environment has the ability to repair DNA damage in the embryo. It appears embryos with genetic damage have the possibility to be repaired in the mother’s body.
This could potentially explain why clients’ transferred with “low grade” embryos go on to have healthy babies? Would a fragmented embryo low on the grading scale (which was transfer and went on to be a healthy baby) be genetically bad by PGD testing standards? We will never know. Research in this area doesn’t exist for PDG testing.
Recently, I read an eye opening article:
A review of, and commentary on, the ongoing second clinical introduction of preimplantation genetic screening (PGS) to routine IVF practice by Norbert Gleicher & David H. Barad
The authors reviewed all research pertaining to PGD testing and came to some eye opening conclusions.
It appears PGD testing for older women and women with poor ovarian reserve or premature ovarian failure may not have increased pregnancy rates. In fact it might be lowering pregnancy rates. Why?
1) Currently PGD testing is performed on day 5 embryos. Older women or women in premature ovarian failure generally produce less eggs during IVF and have few to none embryos on day 5. These women could benefit from day 3 transfer and could go on to become pregnant.
2) Research reviewed pregnancy rates on all women (no separate categories for older and poor responder) who went to day 5 transfer. Women with no embryos on day 5 are eliminated from the research. Thus pregnancy rates do not reflect the whole group. In fact the research has not reviewed pregnancy rates with PGS on poor responders, diminished ovarian reserve and older women.
3) Clinics are diagnosing through embryo quality. Couples are being told to give up and do donor egg as their embryos don’t make it to day 5 or due to poor PGD testing results. Clients are not being told about the option of day 3 transfer, which might benefit them.
I am concerned about couples being sold the miracle of PGD testing, when in fact the research doesn’t clearly state the outcomes. If you are looking into PGD testing please read the research and know your options. I firmly believe in the body’s knowledge. If an embryo has the ability to be restored, a women’s body can do it. It is also important to have your body in balance, so it has the ability to support an embryo’s DNA health. What potentially made the difference for the client in the beginning of the article? Six months of acupuncture and herbs, with lots of focus on successful ovulation and a stable luteal phase. She felt more energetic and calm in her life before entering IVF. One of the many advantages of being well-being and stability in your life.
A review of, and commentary on, the ongoing second clinical introduction of preimplantation genetic screening (PGS) to routine IVF practice by Norbert Gleicher & David H. Barad
J Assist Reprod Genet (2012) 29:1159–1166 DOI 10.1007/s10815-012-9871-2
The current status of PGS
An obvious first argument against current routine clinical utilization of PGS#2 is that authoritative bodies, at present, see no clinical value in PGS [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][7–9]. ESHRE’s previously noted effort to set up a prospectively randomized multi- center study also suggests a healthy level of skepticism, and confirms PGS as an experimental procedure of no proven clinical effectiveness, yet. Published reviews in the literature are confirmatory. PGS utilization to improve pregnancy and miscarriage rates, based on current- ly available data should, therefore, only occur under study conditions, and with appropriate informed consents. Considering the clarity of best available evidence, it is disturbing to witness increasing utilization of PGS, with patients, often, completely unaware of undergoing experi- mental treatments. We have seen patients allegedly advised that the new techniques of PGS#2 offer “their only chance of pregnancy;” and that PGS#2 now represents “routine” state-of-the-art IVF care. We, however, also have seen patients where the failure of PGS#2 was considered evidence enough to advise that their only remaining treatment chance involved donor oocytes. At least two such patients, who failed PGS#2 because none of their embryos reached blastocyst stage, after cleavage- stage, day-3 embryo transfers, and without utilization of PGS, recently conceived at our center with use of autolo- gous oocytes. Both pregnancies are ongoing (Gleicher and Barad, unpublished data). Based on a single small study, by the authors, themselves, described as a “pilot study in need of verification”, two prominent medical journals in the specialty in their June 2012 issues ran an advertisement by a manufacturer touting the company’s DNA amplification system under the head- line “24 sure study shows increased pregnancy rates.” The ad further claimed a 65 % increase in pregnancy rate “even in younger women who are more likely to have favorable IVF outcomes.” Publication of such an advertisements by credible medical journals is, of course, destined to cause confusion.
The misdirection of ongoing studies of PGS#2
Eleven ongoing registered related studies further enhance concerns. Six involve total chromosome comple- ment screening and, therefore, directly or indirectly refer to PGS#2. None, unfortunately, considers in study design the additional variables trophectoderm biopsy at blastocyst stage (days 5/6) adds in comparison to cleavage-stage biopsy (day-3). Blastocyst-stage cultures are meant to select embryos with favorable pregnancy potential. In a Cochrane review Blake et al., however, point out that such an effect is only obtained in so-called good prognosis patients who produce high numbers of 8-cell embryos on day-3. They specifically note that blastocyst culture is not effective in unselected patients or poor prognosis patients.
Whether because of advanced age or premature ovarian aging (POA), diminished ovarian reserve (DOR) results in small oocyte and embryo numbers and poor quality. DOR patients, therefore, very clearly do not represent good prog- nosis patients. They, therefore, cannot be expected to derive outcome benefits from blastocyst-stage in comparison to cleavage-stage embryo transfers. Indeed, the opposite effect can be expected: the poorer a patient’s embryo quality, the less likely will any one embryo reach blastocysts stage. Only a comparatively small number of embryos from older women and POA patients will, therefore, reach blastocyst stage. Women with DOR, therefore, at best, will have only small embryo numbers available on days 5/6 for trophecto- derm biopsy.
The smaller a patient’s embryo cohort at that stage, the higher will be the statistical likelihood that all embryos will be found aneuploid. In other words, two embryos will less likely yield at least one euploid embryo than eight embryos. Combining in women with DOR the risk that none of their embryos will reach blastocyst stage with the increased risk for 100 % aneuploidy due to small embryo numbers, demonstrates why only relatively few DOR patients ever will reach embryo transfer with PGS#2. Quoted pregnancy outcome data, therefore, are highly biased in patient selec- tion because reported data do not report outcomes based on intent to treat. Instead, universally, in all published studies, pregnancy rates were calculated in reference to only those patients who reached embryo transfer on days 5/6, not considering who started the process, and, therefore, exclud- ing most women with DOR.
Unless PGS#2 is utilized only in good prognosis patients, so far only reported in one study by Yang et al., one has, therefore, to consider the possibility, maybe even like- lihood, that in DOR patients embryo culture to blastocyst stage may, actually, reduce pregnancy chances. In such patients a day-3 embryo transfer may result in a viable pregnancy, while the same marginal embryo, cultured to days-5/6, may not survive prolonged culture. As a conse- quence, PGS#2, like PGS#1 before [2–6] in DOR patients may, therefore, actually reduce pregnancy chances. While not formally acknowledged by proponents of PGS#2, their study designs, nevertheless, point towards acknowledgment of such a risk. Scott et al., for example, culture to blastocyst stage only if, by day-3, patients have at least 4 high quality embryos. By excluding from PGS#2 women with fewer good quality embryos, they, obviously, attempt to select favorable patients.
According to Blake et al., four high quality embryos are, however, a low cut-off for good prognosis patients. This makes it very likely that published studies and ongoing clin- icaltrials byScott’s group actuallyrepresent selected goodprognosis patientsintermingledwithpatientsBlake etal. would have classified as unselected, neither representing out- right good or bad prognosis patients. This assumption is further supported by inclusion of patients with “normal” basal FSH levels of up to 12.0 IU/L or even 15.0 IU/L, both FSH cut-offs by most considered at all ages well within DOR range. Being offered PGS #2 may, therefore, harm such patients. Published PGS#2 claims and ongoing PGS#2 trials are, therefore, for at least two very distinct, and opposing, rea- sons, uninterpretable: On the one hand, reported data have excluded some unfavorable patients (<4 good quality em- bryos on day-3); yet, on the other hand, among those who were cultured to blastocyst stage, an unknown number of patients are actually poor prognosis patients, and may in- clude women with DOR. Because they were taken to blas- tocyst stage, their pregnancy chances may, actually, have been reduced.
Reported PGS#2 outcomes, therefore, have to be recog- nized for their limitations. Like early studies of PGS#1, they are uninterpretable, and do not allow determinations which patients would benefit from PGS#2, and who would be harmed. Unfortunately, considering published study designs, currently ongoing clinical trials also will not offer satisfactory answers. One obvious question to be asked is what happens to all those patients who never make it to embryo transfer with utilization of PGS#2? Would they do equally poorly or better, had they not been cultured to blastocyst stage but undergone a routine day-3 transfer without embryo biopsy?
Conclusions
DOR patients represent a significant percentage of patients in most infertility centers. If not properly diagnosed in advance and excluded from PGS#2, young women with POA and older women with age-associated DOR appear at risk to be negatively affected in their pregnancy chances by PGS#2. We noted earlier our anecdotal experience with two older women with DOR. Both had failed up to four IVF/ PGS#2 cycles since they never reached embryo transfer. Both ended up conceiving after day-3 transfers without embryo biopsy and PGS. Anecdotal experiences are, of course, just that! They, however, reemphasize how little is known about the utilization of PGS#2, and how urgently properly designed studies are needed. Unfortunately, current studies in the pipeline do not appear suited to provide needed answers. We have become convinced that PGS in properly selected patient, indeed, improves IVF pregnancy and, likely, also reduces miscarriage rates. We are, however, also, more than ever, convinced that PGS has the potential of reducing pregnancy chances if women are incorrectly selected.
While trophectoderm biopsy and array techniques, unques- tionably, represent significant technical progress, the switch from day-3 embryo biopsy to blastocyst-stage biopsy adds significant additional co-variables. Efficacy of PGS#2 is, there- fore, even more difficult to assess than efficacy of PGS#1. To prevent repetition of the harm caused by PGS#1, it is essential that the clinical utilization of PGS#2 in routine IVF cycles be considered unethical until proper studies deter- mine who the patients are who benefit from such an ap- proach. Acceptance of advertisements by reputable medical journals, claiming efficacy for PGS#2 in improving IVF pregnancy rates, therefore, appears inappropriate. Until pa- tient populations have been defined who will benefit from PGS#2, the procedure should be offered to patients only under study conditions and with appropriate informed consent.
- Acupuncture and Fertility: Does PGS increase pregnancy rates in all women?