Persistence does not pay off! Seek appropriate medical care after 3-4 failures as multiple IVF cycles do not lead to increased chances of having a baby

Posted By Braverman IVF & Reproductive Immunology || 28-Dec-2015

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.

  1. 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.

  1. 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.


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.

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