A new British study published last week in
The Journal of the American Medical Association (Smith_2015.pdf) found that almost two-thirds of patients undergoing IVF
cycles will be successful at or after the sixth cycle, suggesting that
the number of IVF cycles should be extended beyond the usual three or four.
This article has been largely commented by several journals including
The
New York Times, diffusing the same misinformation: “with IVF treatment more is
better”, “keep trying, you will achieve a success” with
as many as nine IVF cycles!
These misleading information will inevitably pressure patients to keep
trying the same failed protocols.
-
False hopes: keep trying, you will finally be successful...
a- The facts
This large study, including over 150 000 women with almost 260 000 cycles
showed that the cumulative live birth rate goes from 29.5% at the first
attempt to almost
66% at the 6th cycle, suggesting to women to never give up as they will be successful if they
keep trying.
The cumulative live birth rate still increased beyond the sixth cycle although
the increase is anecdotical (+2%).
The cumulative live birth rate was shown to be even higher in younger patients
(<40 years old) with up to 70% of success at the ninth attempt while
significantly lower in 40-42 years-old patients (32.7%) and even lower
in women aged >42 years old (16%) when using their own eggs.
In that regards, this study confirms the importance of
maternal age as it directly impacts
egg quality and the chance of a successful pregnancy.
As expected, no differences were seen in women regardless of their age
when donor egg was used.
Further, birth rates were shown to be lower when the male partner was infertile,
and treatment with sperm injections or donor sperm restores the chance
of having a baby.
Interestingly, the number of egg retrieved during a cycle is not predictive
of pregnancy success at the next cycle.
In other words, even if you had no or a low number of egg retrieved during
your current cycle, you can have a baby at your subsequent cycle.
b- Flaws in the study
- Infertile patients are not all the same and should be tracked within specific
infertility cause category:
In the study, patients are considered as a whole regardless of the factors
causing their infertility, that are not discussed at all in the article.
Patient infertility could have multiple etiologies with:
- egg quality issues leading to failed embryo implantation such as in the
Correctible Reoccurring Aneuploid Conversion Syndrome (CRACS, for more
information read our blog, Add the link).
- recurrent pregnancy losses with euploid (normal) embryo (1)
- reccurent pregnancy loss with aneuploid (abnormal) embryo (2-3).
- disorders causing immune related issues (4-7)
Therefore, high risk patients, those with known endometriosis, autoimmune
disease, PCOS or uterine lining issues, should have been followed separately.
- All pregnancy failures are not equivalent
In the same way, the study should have separate patients with failed implantation
that clearly point out an egg quality issue
vs. miscarriage that could also be the results of altered maternal immune
response towards the embryo.
- All embryo losses are not identical
Patients with known euploid losses, either by transfer of PGD normal embryos
or where products of conception were proven to be genetically normal,
should also have been tracked separately as euploid losses are more likely
to occur in patients with reccurent pregnancy loss and require immune
therapies (8-9).
To postulate that persistence does pay off during IVF cycle, this study
must have had broken pregnancy failures into the groups above and followed
patients without treatment to monitor their success through IVF therapy only.
With no doubts, the live birth rate would have been much lower.
By mixing high risk patients with patients having idiopathic losses, that
do not require a particular care, this study might have overestimated
live birth rate.
c- Differences between estimations and facts:
One of the key limitation of all studies looking at cumulative outcomes
with repeated IVF cycles comes from patients who
discontinued treatment.
Large numbers of patients in this study quit the IVF treatments, 34% quit
after the first IVF cycle and
90% of the patients quit the study after the third IVF cycle.
Researchers had to estimate live birth, and assumed that most of the couples
who stopped treatment would have the same chance at having a baby as those
who continued.
But most fertility specialists know that it is
unrealistic for patients to have a good prognosis after several failures (10) as prognosis is worsening with the number of previous failed IVF
attempts (11).
Nevertheless, they also used a conservative estimation considering that
patients who did discontinue IVF treatment won’t have a successful
pregnancy.
This is a fact and the
best approach to us as it reflects the poor prognosis with repetitive IVF attempts which simply
means that patients underwent recurrent pregnancy failure.
With the conservative approach, the cumulative live birth rate is, indeed,
far less outstanding.
Overall, at the sixth attempt this rate reached 46.8%. In younger patients,
it reached 50% while we have 19.2% and 5.6% for the 40-42 years old and
>42 years old category, respectively.
In this study, the authors assessed IVF success by combining “all
embryo transfer events after an ovulation stimulation into 1 analysis
unit”, which can significantly and artificially increase the rate
of pregnancy.
Unlike the majority of studies that calculate pregnancy success per transfer,
in the present work, a successful pregnancy could be the result of several
rounds of embryo transfers if you were lucky enough to have multiple good
quality embryo after one single ovarian stimulation.
If we consider the conservative estimation, this study showed the lack
of significant benefits after four IVF cycles as live birth rate stagnates
at 46% after four cycles, regardless of the patient age category.
After four cycles, patients should indeed begin to consider looking into
other options and not, as the article suggests, keep trying.
- Persistence? Yes, but with adequate care that will look for your infertility’s
causes and put in place a strategy with tailored-design therapies
Although the study did include patients with pathologies such as PCOS and
endometriosis, known causes of immune-related infertility, it did not
mention the therapies used, if any, during these IVF cycles.
If your immune issues impact your egg quality, it is more than likely
that they will also negatively affect your endometrial receptivity and
your chance of having a successful pregnancy despite the use of an egg
donor as seen in euploid losses.
Fighting the increasing burden of female sterility could not be done by
multiplying the number of IVF cycles, blindly, with no analysis of the
underlying causes leading to these repetitive pregnancy failures.
This will simply lead to patients being drained physically, emotionally
with a substantial sacrifice of their financial resources.
It is more than likely that patients with success after six cycles or even
more cycles might have had success in far fewer cycles with adequate therapies.
Besides, with no therapy, these successful patients may have suffered
from obstetrical complications although this point was not discussed in
the study.
Treating patients suffering from infertility with IVF should require a
thorough diagnosis and subsequent adjusted therapies.
At
Braverman Reproductive Immunology, all our patient undergoes a battery of tests including a complete immune
testing to determine the possible causes of infertility and determine
the therapy (surgery, immune therapies) they might benefit the most from.
In addition, we do monitor these parameters through the pregnancy, to
detect any alterations that could potentially trigger pregnancy complications.
This allows us to adjust our treatment in a timely manner and give you
the best chance of having a healthy baby.
References
1- Stephenson MD, Awartani KA, Robinson WP. Cytogenetic analysis of miscarriages
from couples with recurrent miscarriage: a case-control study. Hum Reprod.
2002 Feb;17(2):446-51.
2- Hodes-Wertz B, Grifo J, Ghadir S, Kaplan B, Laskin CA, Glassner M,
Munné S. Idiopathic recurrent miscarriage is caused mostly by aneuploid
embryos. Fertil Steril. 2012 Sep;98(3):675-80.
3- Sugiura-Ogasawara M, Ozaki Y, Katano K, Suzumori N, Kitaori T, Mizutani
E. Abnormal embryonic karyotype is the most frequent cause of recurrent
miscarriage. Hum Reprod. 2012 Aug;27(8):2297-303.
4- Aris A. A 12-year cohort study on adverse pregnancy outcomes in Eastern
Townships of Canada: impact of endometriosis. Gynecol Endocrinol. 2014Jan;30(1):34-7.
5- Qin JZ, Pang LH, Li MJ, Fan XJ, Huang RD & Chen HY. Obstetric complications
in women with polycystic ovary syndrome: a systematic review and meta-analysis.
Reproductive of Biology and Endocrinology 2013 11 56–70.
6- Brouwer J, Laven JS, Hazes JM, Dolhain RJ. Brief Report: Miscarriages
in Female Rheumatoid Arthritis Patients: Associations With Serologic Findings,
Disease Activity, and Antirheumatic Drug Treatment. Arthritis Rheumatol.
2015 Jul;67(7):1738-43.
7- Sugiura-Ogasawara M, Ozaki Y, Kitaori T, Kumagai K, Suzuki S. Midline
uterine defect size is correlated with miscarriage of euploid embryos
in recurrent cases. Fertil Steril. 2010 Apr;93(6):1983-8.
8- Boots CE, Bernardi LA, Stephenson MD. Frequency of euploid miscarriage
is increased in obese women with recurrent early pregnancy loss. Fertil
Steril. 2014 Aug;102(2):455-9.
9- Morikawa M, Yamada H, Kato EH, Shimada S, Yamada T, Minakami H. Embryo
loss pattern is predominant in miscarriages with normal chromosome karyotype
among women with repeated miscarriage. Hum Reprod. 2004 Nov;19(11):2644-7.
10- Ogasawara M, Aoki K, Okada S, Suzumori K. Embryonic karyotype of abortuses
in relation to the number of previous miscarriages. Fertil Steril. 2000
Feb;73(2):300-4.
11- Maconochie N, Doyle P, Prior S, Simmons R. Risk factors for first
trimester miscarriage--results from a UK-population-based case-control
study. BJOG. 2007 Feb;114(2):170-86.