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Is unexplained infertility always what it seems? The role of laparoscopy in IVF overuse

Agni Pantou, M.D., Ph.D(c)
MD, PhD Candidate in Obstetrics and Gynaecology

Category:
Failed IVF Cycles, IVF Abroad

Laparoscopy and its role.
From this video you will find out:
  • What is a real definition of an infertile couple?
  • What is unexplained infertility?
  • What are the official guidelines for couples facing unexplained infertility?
  • Laparoscopy or IVF?
  • What can be found with laparoscopy?
  • Endometriosis – how to treat it?
  • Why do we insist on IVF overuse in patients with unexplained infertility?

 

Laparoscopy or another IVF?

In this session, Agni Pantou, M.D., Ph.D. Candidate in Obstetrics and Gynaecology at the University of Athens, Physician & Surgical Assistant at Genesis Athens Clinic has been talking about unexplained infertility and the role of laparoscopy in IVF.

Understanding fertility and infertility

Firstly, Agni Pantou first addresses the concept of fertility and the particular outcomes that most couples will achieve pregnancy within one year of trying due to a great likelihood of conception occurring during the first months. On the other hand, there is a small percentage of couples (5-7%) that will conceive at the beginning of the second year.

Infertility is defined as failure to achieve pregnancy after:

  • 12 months of regular unprotected intercourse in women below the age of 35.
  • 6 months of unprotected intercourse in women above the age of 35
  • Infertility affects up to 15% of couples

Unexplained infertility – definition

If the specific regular timing for every couple has already passed, an infertility investigation that is based on standards and tests should be the next step to further determine the plausible causes of infertility. Those procedures are as follows:

  • Assessment of Ovulatory Function: The individual hormones should be tested (Hormonal profile)
    • FHS
    • Luteinizing hormone
    • Estradiol
    • Progesterone (depending on the cycle)
    • Patency of fallopian tubes ( hysterosophilography) checks for:
      • Any abnormality seen in the uterine cavity
      • The patient’s tubes (Partial or full blockage of tubes or other abnormalities like hydrosalpinx )
  • Investigation of the male factor- (Sperm diagram)
    • Morphology
    • Motility
    • Concentration

Prevalence

It is estimated that a percentage of 15% of couples do have infertility issues, while another 40% of patients are said to have unexplained infertility after undergoing the steps that entail the standard infertility investigation. Additionally, there is a percentage of 80% of these patients with unexplained infertility that are found to have an unidentified cause, such as a pelvic floor abnormality. Finally, the remaining 15-20% of patients would have unexplained infertility.

Official guideline for couples facing unexplained infertility

Even though existing guidelines are given by official organizations such as the European Society of Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Medicine (ASRM), there is still a lack of evidence because of a shortage of robust data.
Therefore, the combination of impatience for the completion of cycles along with no specific guidelines usually leads to undesirable outcomes such as mismanagement of their clinical situation for instance.

The National Institute of Health Care guidelines for unexplained infertility suggest that couples are expected to undergo expectant management that involves:

  • Couples under the age of 35 should try to conceive naturally via regular unprotected intercourse for 2 years.
  • For couples above the age of 35, both times intercourse and 3 and up to 6 intrauterine insemination attempts. In case the procedure remains ineffective, IVF treatment is recommended, or performing diagnostic laparoscopy.

Laparoscopy or IVF – which is next?

There are no clear guidelines on whether to proceed with IVF or Laparoscopy. It is only suggested to consider various factors for each case.

On one hand, IVF treatment can be considered. However, couples with unexplained infertility typically have a lower success rate with IVF compared to cases where infertility causes are identified. Additionally, diagnostic laparoscopy is also an option, despite being a minimally invasive surgery.

Laparoscopy

Laparoscopy is a procedure that allows one to see the uterus inside, a thin lighted tube that has a video camera which is called a laparoscope is used. The following conditions and diseases can be found during laparoscopy:

  • Endometriosis, which is the presence of endometrial tissue and stroma outside the endometrium.
    • Affects 10% of reproductively healthy women.
    • 20-25% of the cases are asymptomatic.
    • Laparoscopy is the most effective way for diagnosis.

The treatment of such diseases still remains controversial, which leads to patients being misdiagnosed.

The signs and symptoms of endometriosis are commonly associated with pain and infertility is simultaneously said to cause the following conditions:

  • Adhesions
    • Altered tubal mobility
    • Altered tubal-ovarian relationship
    • Altered systemic immune response
    • increased macrophages, cytokines, anti-endometrial antibodies
    • corpus luteum deficiency

As regards fertility, the immune response is known to cause impaired fertilization and implantation, as well as compromising embryo quality and development.

Endometriosis can be classified into 4 categories:

  • Category I (Peritoneal endometriosis)
  • Category II (Ovarian endometriomas)
  • Category III (Deep Infiltrating Endometriosis I)
  • Category IV (Deep infiltrating Endometriosis II)

Category I indicates there are small black spots in the Douglas space, the cul-de-sac. Category II would also affect the ovaries. For example, ovarian endometriomas as well as spots seen in different places in the pelvic floor. Category II would be deep infiltrating endometriosis, which involves organs within the pelvic cavity, including the rectum and the uterus. In some cases, it would cause a frozen pelvis, where all the organs are stuck together because of adhesions formed due to endometriosis. Category IV is deep infiltrating endometriosis, which would be an extreme form involving organs both within and outside the pelvic cavity, including the bowels, liver, and even the brain. It’s the most severe form of this disease.

According to ASRM:

Laparoscopy is indicated when there is evidence or a strong suspicion of endometriosis, pelvic adhesions, or significant tubal disease. Laparoscopy should also be considered before applying aggressive empirical treatments involving significant costs and potential risks.

According to ESHRE:

There is still considerable debate regarding the place of laparoscopy for cases of unexplained infertility.

These two quotes illustrate how big the debate still is. It has been voiced, that laparoscopic surgery should not be part of the standard infertility investigation. The operating protocol for endometriosis-related infertility, especially as the therapeutic benefits of the intervention cannot be foreseen or guaranteed. So, patients with unidentified infertility etiology may be treated with IVF, despite several studies indicating that these patients may have a strong potential to achieve natural conception following a conclusive and definitive infertility investigation.

Laparoscopy – research

In 2019, the research team from the Genesis Athens Clinic collaborated with the Medical School of the National and Kapodistrian University of Athens on a study aimed at assessing the efficacy of diagnostic laparoscopy in women experiencing infertility or with undiagnosed causes according to standard infertility assessments. This prospective cohort study involved 107 women, each having undergone at least three in vitro fertilization (IVF) attempts, meeting the criteria for recurrent implantation failure, and displaying a baseline elevation of CA 125, suggesting potential underlying conditions like endometriosis or pelvic inflammation.

The results showed that out of the 107 patients, 62 were diagnosed with endometriosis, and they were encouraged to conceive naturally. This constitutes 58% of the patients, highlighting a significant proportion. Among these, 48% successfully conceived naturally within the first year post-surgery. It’s worth noting that most pregnancies in this group occurred within the first six months, 93.5%, resulted in live births.

For the remaining cases:

  • 25 out of 107 were diagnosed with adhesions and also advised to conceive naturally
  • 11 achieved a natural conception
  • the remaining 20 cases fell under the subgroup of unexplained infertility and proceeded with a single IVF cycle and among them, 20 patients achieved a clinical pregnancy

Another study examined mild male infertility and recurrent implantation failure, concluding no direct link. Laparoscopy diagnosed 42.5% with endometriosis, 22 with adhesions, and left 36 cases unexplained.

Dr Mara Simopoulo’s and her colleague’s research warns against diagnosing endometriosis late, which can lead to recurrent implantation failure and excessive IVF use. Though data on unexplained infertility is limited, studies like Dr Sarah Mustafa’s from 2020, emphasize the incomplete understanding of recurrent implantation failure and highlight the importance of diagnostic and therapeutic challenges such as laparoscopy.

Conclusions

To conclude, unexplained infertility diagnoses appear to lack any identifiable reasons behind them, posing the question: when or through which investigations do we give this diagnosis? Addressing this may help reduce IVF overuse and recurrent implantation failure. Besides, according to an article by Muhammad Reza Sadeghi published in 2015in The Journal of Reproduction and Infertility, just because there is an inability to identify what leads to fertility does not mean that it is absent. Such approaches, for instance, diagnostic laparoscopy, can be very important in preventing the overuse of IVF and improving outcomes.

- Questions and Answers

I know that I have partially blocked tubes and endometriosis, but hydrosalpinx was never mentioned. Should I further investigate this after 4 failed ICSI attempts? I have had a laparoscopy.

It depends on what we mean by partially blocked tubes. Is it one of the tubes that are blocked, or under pressure, they open? However, if you’ve been through failed IVFs and ICSI transfers, I assume that you’ve been through an embryo transfer as well, or had a failure before that. I mean there are many different factors like if there was an implantation failure or did it failed at the fertilization stage because there is also the genetic factor, for example. If there were hydrosalpinx, the doctor for sure would have suggested removing the hydrosalpinx as it’s a very big factor to fail. I assume the endometriosis was diagnosed and treated by cauterization of the spots. It depends on how big the extent of endometriosis was, there is also a stop of the period to eliminate the very small spots that the surgeon cannot see. As you already had a laparoscopy, you don’t need it again. If you had hydrosalpinx, then the doctor would have seen that. Endometriosis should have been cured. I assume there are also other factors that you should check as well.

Can PID (Pelvic inflammatory disease) only be found via laparoscopy? Are there other tests?

If there is acute inflammation, so the patient would have big pain. In general, if PID is chronic, then it’s only seen under laparoscopy. An ultrasound would suggest there is a suspicion of adhesion, or hydrosalpinx could be seen. However, if there are no symptoms at all and just a chronic pelvic inflammatory disease, then it’s only seen by laparoscopy. It depends on if it’s acute or chronic inflammatory pelvic disease.

I am 35, I have had 5 fresh IVF cycles. My 5th attempt lead to a chemical pregnancy and 1 FET. I had a natural ectopic pregnancy after my 2nd failed IVF. I had laparoscopic surgery and was told I have endometriosis. I have another laparoscopy on Wednesday. I have 3 embryos frozen. What FET protocol would you recommend for endometriosis? I had an HSG, and both tubes were fine.

I assume that you had another laparoscopy because of the natural ectopic pregnancy. I assume you had a salpingectomy, so in that case, there’s always a bigger chance of having another ectopic pregnancy if there was already one. Either way, there is a little increase in the percentage of ectopic pregnancy after IVF. If you’ve had already a history of ectopic pregnancy and salpingectomy, however,  If endometriosis is there, it would be best if you also checked the uterine cavity. To see if there is some sort of endometritis if you haven’t done so already. It’s checked via biopsy of the uterine cavity, and if there is endometritis – there are certain antibiotic protocols that are used, and they’re out there to treat that before the next embryo transfer takes place. At least to increase the chances that everything is all right in the uterine cavity. I assume that you’ve also checked the genetic factors as well. As you have already had an ectopic pregnancy, there is a slightly increased risk to have another one because of having the ectopic pregnancy in the first place, but it all depends on why you had an ectopic pregnancy. If it was because of chronic salpingitis that has changed the morphology of the tubes, or it just happened. There is always a risk of an ectopic with IVF? You are a bit more prone in case of salpingitis, so I guess with the laparoscopy that you will soon do, they will check the pelvic floor, and then I would highly suggest checking for endometritis too. If the tubes are fine, the hysterosalpingography will show that they’re open, but if there is an alteration in the epithelium of the tubes, it is not visible via salpingography. It could happen because of a pelvic inflammatory disease or some kind of infection from the genital tract that alters the epithelial cavity. Those are tracheitis, endometritis, salpingitis, etc., all of them are kind of related. If you’ve been through some kind of infection at some point, and I don’t necessarily mean an infection, such as ureaplasma or mycoplasma, which could be the case as well. In case the flora is disturbed, then the naturally existing bacteria that we have in our epithelia could even cause a chronic inflammatory state. I would say that having a little sample from the uterine cavity checked to see if the flora is okay or not would also trigger the idea that maybe there is an inflammation that has gone through with your tubes, and if possible, treat it with antibiotics.

Is there still an increased risk of ectopic with IVF after ectopic even where the tube was not removed? If yes, does IVF cause the increased occurrence of ectopic just for that round or for natural attempts also following IVF? I don’t have any known reasons for ectopic.

There is always an increased risk of ectopic pregnancy after IVF, and to a very big extent, that is because when we do the embryo transfer, the tubes are open, so when the embryo goes from the uterine cavity, there’s a chance that it goes through the salpinx. Then the salpinx and its layer push it back to the uterine cavity with the cilia. If these cilia in the epithelium of the tubes are affected, the embryo is stuck in between the cilia and the affected layer of the tube. This is how ectopic pregnancy occurs. If you’ve had an ectopic and if the tube was not removed, the risk is again the same. If there is an affected tube because of inflammation, endometriosis, or adhesions surrounding the tubes, which are changing the tube’s ovarian morphology and texture, there is always an increased risk, even in natural conception. IVF has just its own risk of an ectopic.

My doctors told me that IVF ‘bypasses’ endometriosis. My understanding now is that endometriosis can lead to both poor egg quality and failure to implant. After 3 failed transfers with poor quality eggs, I am finally getting treatment for endometriosis (GnHR suppression). What else can I do to make implantation more likely after the suppression? The wait for laparoscopy in my country is over 9 months currently and not available privately – suppression is my only option.

As I said, endometriosis does cause poor quality of the oocytes and poor fertilization rate, poor implantation rate. IVF does bypass the endometriosis to a very big extent, but not necessarily it would cause a poor quality of the oocytes. With supplements of estradiol and progesterone in case of the corpus luteum deficiency that is caused by endometriosis then, implantation, if it takes place, could be supported. There is a small percentage that endometriosis affects IVF, not a big percent. That’s why your doctor has told you that IVF surpasses endometriosis, but it does. As I said in the presentation, after certain attempts of IVF, instead of going through another and another psychologically wise, body-wise, and cost-wise it doesn’t make any sense. There should be something there, an underlying disease such as endometriosis that should be cured. In order to investigate everything, a laparoscopy would be suggested, but it all depends on the age. If a woman is 40 years old and older, for example, it could be suggested again to have a laparoscopy. There is also the poor quality of the eggs because of age, so it depends, we put many factors together to make a conclusion and suggest to go through laparoscopy. Not all patients go through that, mainly younger women, but of course, women after recurrent implantation failure of older age, but the hormonal profile is very important to see that is fine, we would not suggest laparoscopy to everyone. As you’re getting treatment for endometriosis by suppression to help you with an answer, I would need to know your age, I would ask how is your hormonal profile before suppressing, is the AMH fine because suppressing for a few months could also suppress the hormonal levels more, which would not be good as well. Even if you would go for IVF later on, so I would ask all these questions before giving a final answer.

What’s the success rate for donor eggs and good quality sperm at your clinic (Genesis Athens)?

I would say it is a 75% success rate with donor eggs and good quality sperm.

I had an egg collection the other day, and the clinic did the biopsy for PGS (NGS) on day-3. Now, I heard someone say that day-5 is better. What are your thoughts? I only got 3, 8-cell, 3-day embryos. I’m 41 years old. What are the chances of at least one good enough embryo for transfer?

There is a possibility of checking day-3 embryos and have a biopsy on them. However, a biopsy at day-5 or day-6 during the blastocyst stage is mostly used. There is less risk of damaging the embryo during the biopsy itself. You need to wait for those results from the biopsy that you already had, and the doctor will guide you through the next steps, or else you can always try day-5 preimplantation screening. When we do PGS, it’s always better to have many embryos because from the biopsy and the screening, there are many different outcomes, so having a higher amount of embryos that are being tested, you’ll have a higher amount of embryos, that would be okay. The embryo transfer would be with 2 or 3 embryos at your age. There is a chance that even at least one embryo is good enough for transfer, and if everything else is fine, then the percentage of success rate could also be fair, it doesn’t have to be 2 or 3 embryos to have a good result, you just, increase the chances.

I have low AMH and only 1 tube now from the ectopic pregnancy. Have you seen patients with 1 tube, low AMH, and recurrent implantation failure with 6 IVF transfer conceiving naturally after a laparoscopy? I have 2 x day-6, 5AA hatching embryos, and 1 x 4BA embryo, with me being 35 and 6 failed transfer some were double transfer. Would you recommend transferring 3? Which one is better?

It’s quite difficult, I would say having a natural conception with all these factors. There is always inflammation in our mind because of the ectopic pregnancy and the recurrent implantation failures. I would say that you should keep going and have another attempt and check with your doctor if there is anything else you could do with the implantation failure before doing the embryo transfer. There is another test that you could check, which is the ER Map, or the ERA test, which would suggest the window of implantation, and by having this test, the physician would be more sure when to do the embryo transfer. You could also combine a biopsy sent for the ER Map with a biopsy sent for endometritis, and this is how you would have two biopsies but done in one day, and then you would know when the window of implantation is good, so the medication would be given accordingly. NK cells you don’t really need to check I think, they’re not as high in the priority list of tests. There’s a very big debate about NK cells right now. If there is endometritis, you would cure it before you do the embryo transfer, and that will increase the success. That’s what we see almost every day in our clinic, we go through this protocol in those cases.

I have heard that my hormone levels are good, but I have PCOS. Does that mean that I should get many but bad quality eggs? I only got 6 eggs in my retrieval (5 mature).

If your hormone levels are good, PCOS is a whole other chapter, it could cause the low quality of eggs, not necessarily but there is a chance that the eggs are affected, but if the hormonal levels are good, they’re not disturbed, then the chances of affected oocytes from PCOS are also getting lower. At the end of the day, if you have 5 mature eggs, then go ahead, you only need one to be implanted in your case, and I’m sure that your physician would take care of the whole picture of the PCOS. There are many different protocols for patients with PCOS, like slowly gathering the mature ones and then fertilizing them, depending on all the other factors that are surrounding your case, the embryo transfer should be successful.

Does your clinic (Genesis Athens) have an embryo adoption program?

Yes, we do. There is a consent that the patients are signing when they start with IVF. One of them would be to donate the embryo for research another would be to discard it. We are really trying to also promote an embryo adoption program. I would actually like to evaluate this with the law department of our clinic and get back to you with some more details as well.

How does high testosterone impact fertility? I had normal levels, although I have recently introduced DHEA supplement 25mg, and I am worried this will increase the testosterone level. I will have it retested.

A high level of testosterone could impact folliculogenesis, it could impact the quantity and quality of the eggs as well. DHEA is given sometimes as treatment, and it could help, but it all depends on what the level of testosterone already is, so in the case, of PCOS, for example, if that is the reason for high testosterone because there are many other reasons endocrinologically wise, I would suggest to have it tested simultaneously with a gynecologist and an endocrinologist so that they can see it and help you within with the levels of testosterone, it could certainly affect it.

I did hormone tests in March and the retrieval in December, and in between, I started the pill, took maca powder, etc. Could my hormone levels have changed, which might have a negative impact on my treatment? I am 41.

It wouldn’t have a negative impact on the treatment, this is not the reason why the treatment was not successful to a big extent, it could help, but it wouldn’t sabotage the retrieval or the treatment. There are other reasons for that, mainly because of the age and the oocytes and the DNA of the oocytes gets slightly affected, and after the age of 40 the mutations are even higher, and there are more poor quality oocytes, it doesn’t mean that they are not mature ones and not good, but there’s a higher risk of having a poor quality oocyte resulting in the failed attempt.

My testosterone level was 1.24nmol (range 0.29 – 1.67), and my DHEA-s level was 4.89pmol (range 1.65 – 9.15). With 25mg, is this likely to increase testosterone above normal levels?

Not necessarily, but it depends on the other hormonal levels and the reason why testosterone would be affected. If it’s PCOS or another reason for that, what other symptoms are there? It wouldn’t affect it as much, but endocrinologists would certainly, answer this question better, I’m sure.
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Authors
Agni Pantou, M.D., Ph.D(c)

Agni Pantou, M.D., Ph.D(c)

Agni Pantou, M.D. is a PhD Candidate in Obstetrics and Gynaecology - Second Department of Obstetrics and Gynecology at Aretaieion Hospital - Medical School of The National and Kapodistrian University of Athens, Department of Physiology of medical School of the National and Kapodistrian University of Athens, and “Genesis Athens Clinic” Private General Gynaecological Clinic of Athens.
Event Moderator
Caroline Kulczycka

Caroline Kulczycka

Caroline Kulczycka is managing MyIVFAnswers.com and has been hosting IVFWEBINARS dedicated to patients struggling with infertility since 2020. She's highly motivated and believes that educating patients so that they can make informed decisions is essential in their IVF journey. In the past, she has been working as an International Patient Coordinator, where she was helping and directing patients on their right path. She also worked in the tourism industry, and dealt with international customers on a daily basis, including working abroad. In her free time, you’ll find her travelling, biking, learning new things, or spending time outdoors.