By fertility experts from Spain.
In this session, Dr Andreas Abraham, MD, double board-certified in Obstetrics and Gynaecology/Reproductive Endocrinology and Infertility, The Head of Eugin International Clinic in Barcelona, Spain, has been discussing uterine most important uterine factors that might impact or have an effect on fertility.
Dr Abraham started his presentation by explaining the definition of infertility: the inability of a sexually active couple who does not take contraceptive measures to achieve a spontaneous pregnancy within one year. This definition of 12 months applies to women under 35. If it is patients who are over 35, which by definition is already advanced maternal age, then this would be six months. If you look at infertility worldwide, it applies to 15% of couples at reproductive age, which accounts for 50 to 80 million women worldwide.
Talking uterine factor infertility, that would apply to around 10% of cases of infertility. If you look at the uterus, there are different players, and obviously, we have a limited time frame.
In general, we can further divide uterine factor infertility into:
Polyps are an overgrowth of the endometrium, which extends into the uterine cavity. Usually, these structures are benign. The diagnosis starts with an ultrasound, either 2D or 3D ultrasound. If there is a suspicion of a polyp, then the second line diagnosis would be a Hysterosonography, also called Sonohysterography, which means that the doctor would inject a small amount of sterile cell line into the uterus cavity to study the lining of the uterus. It’s best to perform it one-week post-menstruation, and that provides a clear picture.
The third line diagnostic would be a hysteroscopy, which is a minimally invasive procedure. We use a hysteroscope, a very tiny telescope with light. Most of these hysteroscopes have a second channel where you can insert instruments to operate. The big advantage of hysteroscopy is that you can see, diagnose and treat it at the same time.
The surgical treatment is rather easy, you just scrape them off, and that’s it. The indication for surgical treatment depends on symptoms and size. If there is a polyp of over 5 millimetres, you would usually act on it. Especially, if you have a patient who has already had some cycles and some problems before IVF or ART cycles. That would be a clear indication to be acting on the presence of polyps.
Uterine fibroids, so-called leiomyomas, are benign tumours that arise from the myometrium of the uterus. They are usually surrounded by an extracellular matrix in uterine leiomyoma and are categorized by their location. There are fibroids located on the outside of the uterus and inside the uterine wall. There are the ones that are submucous, under the uterus lining and reaching into the cavity.
They are quite frequent in the general population since the trigger for the growth of fibroids is estrogen, so the growth increases with maternal age, and they can cause symptoms that go from painful periods, bleeding and infertility. The detection of fibroids is quite frequent in ART treatments. They are found in 5 to 10% of infertile patients. They may be the sole cause of infertility in 2-3%.
As Dr Abraham mentioned, there are 3 different types of fibroids, and the ones that should be treated are submucosal, so the ones found in the cavity, touching or even distorting the endometrial lining. And also the ones that are in the wall but distort the endometrium and the ones that cause symptoms.
The ones that are subserosal, so the ones outside the uterus. For those, there is no need for surgery. At least you do not touch them in the context of reproductive treatment.
The fibroids found in the uterine wall, again, you usually do not touch. There is controversy from which diameter you would remove them, and the cut-off level is 4-5 centimetres.
In terms of non-surgical treatments, medical treatments, there are still quite limited options. There is the option to use GnRH agonists. The most common is Decapeptyl, an intramuscular injection, which blocks ovarian function. It puts you into artificial menopause, blocking the function of the ovaries, meaning to stop the production of estrogen since fibroids grow by stimulated estrogen, which dries them out in a way. That is usually a treatment that lasts between 2 and 3 months.
Dr Abraham also added that lately, there was a drug called Esmya, unfortunately, The European Medicines Agency (EMA) put it on hold since this drug, which is a selective progesterone receptor modulator caused significant and severe liver damage. Therefore, they put it on hold, so it is not available as a project option at the moment.
Hysteroscopy, where we are inserting telescope-like, very tiny structure instrument, usually 8-10 millimetres in diameter in the cervical channel reaching into the cavity. Most of these have a second channel where you can insert surgical instruments, and you could immediately treat what you see. You could get a polyp out, or you could get a fibroid out, that depends on the size and location of the fibroid. A polyp is easy to reach, a fibroid might be more tricky, and if the fibroids are too big to be operated on transvaginally, then the next step would be a laparoscopy
Laparoscopy, a minimally invasive procedure where you insert a similar instrument through the umbilicus, the camera would be inserted with the light, so you can see around. Then, usually, 2 surgical instruments would be inserted. In the end, you end up with 3 tiny incisions, and one could operate on a fibroid or other structures at the outside or inside the wall. If that would not be possible in terms of very obese patients or if there are adhesions that obstruct this way, then the last resort would be to do a surgical incision, a caesarean type incision and open the abdomen or the pelvic region up. It would be an open surgery on the uterus. Laparoscopy is still the gold standard procedure.
One of the alternative options is so-called Uterine artery embolization (UAE), where you inject small particles via a catheter into the bloodstream to block the blood supply of the uterine artery. You block the blood support, and that kind of dries out the fibroids. This procedure is done for the treatment of uterine fibroids and the located form of adenomyosis.
The second treatment that came up lately is the so-called High intensity focused ultrasound ablation of uterine fibroids (HIFU), which is getting popular since it’s a non-surgical and minimally invasive procedure. It shows good results, but we do not have a lot of data yet, and there seems to be a quite high recurrence rate.
According to Dr Abraham, we need to enumerate Müllerian duct anomalies (MDAs), which are not very frequent but can be a treatable form of infertility. Patients who have these anomalies, who are born with these, have a high incidence of infertility, high incidence of repeated first-trimester loss, and high incidence of intrauterine growth retardation, high incidence of pre-term labour.
Dr Abraham emphasized the female reproductive tract develops from these Müllerian ducts. They appear in the very early development of the fetus and the fallopian tube, the uterus and the cervix, plus the upper two-thirds of the vagina derive from these Müllerian ducts. They have a frequency of 1 to 7% in the general population, and they account for 5 to 10% of patients who repeated pregnancy loss (RPL).
The most frequent forms are the septated uterus, the bicornuate uterus and the arcuate uterus:
This is the most common anonymity found in infertile women requiring ART treatment. That means that there is a skin-like wall in the uterine cavity, dividing the cavity into two compartments. It can account for 1st and 2nd-trimester pregnancy loss and is associated with uterine infertility. The solution is the operation, resection/ the ablation of this structure via hysteroscopy.
It is similar to the septate uterus, but the septum is more extreme, dividing the uterine cavity into two different mini cavities. It accounts for problems in the 2nd and 3rd trimesters and prematurity. It rarely requires treatment.
Adenomyosis is characterized by the presence of endometrial tissue within the myometrium. It has an incidence of 20 to 35% of women in the reproductive age. It is more and more frequent in the 4th and 5th decade of life, and since we see more and more women in advanced maternal age, it is becoming more common. Dr Abraham added that half of the patients for IVF is 40 plus.
The symptoms range from pelvic pain, painful periods to abnormal uterine bleeding and infertility. It can impact IVF outcomes in terms of reduced implantation and clinical pregnancy rates, increased miscarriage rates and decreased live birth rates.
Dr Abraham also advises that it’s important to state that you cannot diagnose adenomyosis solely by ultrasound, you would have to do an MRI to confirm it.
There are two different forms, there’s the focalized adenomyosis, which sometimes can resemble a fibroid. And there is diffuse adenomyosis, meaning it is spread all over the users.
The mechanisms with which adenomyosis might impair fertility are:
In a lot of cases, it’s asymptomatic. You diagnose it, but it has no impact on the capacity to have natural pregnancy or IVF outcomes. Treatment is tricky. Surgical options apply just to the focalized adenomyosis that resembles or might resemble a fibroid. The diffuse form is very tricky to treat, and there’s just one treatment option using a 3-month course of GnRH agonists, Decaptetyl.
Dr Abraham also informed that:
‘Adenomyosis is more, and more diagnosed because we have more and more advanced age patients. 55%, in our case, of the IVF patients who go ahead with their own eggs are 40 years and older, so this accounts for a big part of our patient population.’
I assume that you had four unsuccessful IVF cycles with your own eggs. Endometrial scratching is a very interesting topic that came up around about five, six years ago by accident. A group in Israel noted that in patients where they did a hysteroscopy before the IVF cycle, there were higher implantation rates. Endometrial scratching means irritation of the endometrium before the IVF cycle.
In the beginning, everybody was very excited about this finding, it triggered a lot of studies all around the world, hoping to have found a very potent means to increase the implantation rate. That means you irritate the endometrium, scratch the endometrium, you do that with a little catheter, you use the speculum, get into the womb scratch around the clock. You will irritate the endometrium without provoking bleeding, and then you’d have the IVF cycle.
If you look at evidence-based medicine, all the studies that have been performed and there were a lot in the last five, six years now recently have shown that there is not a measurable effect. It doesn’t hurt, but if you look at the evidence-based data, we can’t tell that it will improve your chances. In our clinic, we try to be very strict and be as evidence-based as possible. We used it at the beginning, after having heard about this in the last two years, we refrained from it since the latest data doesn’t support it anymore. Don’t worry, it is something your doctors tried since you had four unsuccessful tries so far, and I know how frustrating it is in terms of infertility in general, it’s very tricky to find a sole responsible factor. It is a multi-factorial procedure and process, so it’s very rare to find the one solely responsible factor.
The first step, as I told you, is the ultrasound. Polyps are tricky, and on the ultrasound, you can see very tiny structures, but sometimes you see artefacts. It might be, and it’s not the fault of your gynaecologist or the sonographer, it might show up and seem to be a polyp but then if you dig deeper into it, do the sonohysteroscopy or even hysteroscopy, you might not find it because it was an artefact.
Polyps are not always visible on ultrasound that’s why you have to do this three-step diagnosis. If you see a polyp on an ultrasound, you might want to verify it with the ultrasound using the injection of the cell line. That might make it more visible, and if you confirm it, then you go and get it out with the hysteroscopy.
Usually, if you block the ovarian function, it’s reversible. The artificial menopause that’s created is reversible, it would not put you in a permanent state of menopause, and it won’t lower your antral follicle count or AMH level. This is age-dependent. Usually, the effect of these injections is around two months. These injections are used in the treatment of endometriosis. All the alterations and problems that are triggered by estrogens, endometriosis, adenomyosis and fibroids, the concept of treatment is at some stage to block the production of estrogen to run down the system in the ovaries, but this is reversible, so it is temporary.
The presence of ectopic endometrial tissue, which is by definition what I told you in the context of adenomyosis which is closely or very much linked to deep endometriosis, goes together but can contribute to ectopic pregnancy. If you have this problem, the transport of the egg or the embryo can be impaired, it’s a mechanical thing. There can be a link between them. The pelvic pain is also related to that, so the symptoms to have pelvic pain are related to what you described, so yes.
AMH can show some fluctuations as well, yes that is something which you can regard as in the normal range.
Yes, the differential diagnosis is quite tricky. Sometimes, it’s just a slight septum, or it’s a very long septum. Differentiating between a septate uterus and a bicornuate uterus is not that easy. Since you had a hysteroscopy, some of this septum has been cut off. The best way is to combine both. Look from the inside of your abdomen to the outside of the uterus and inside by hysteroscopy. Working from both ways would be the way to go. Remember, bicornuate uterus very rarely requires an operation. The spontaneous conception rate in women with a bicornuate uterus does not decrease. It is a problem later on in pregnancy, second trimester, third trimester, preterm labour, prematurity.
The topic of adhesions post-op is very tricky. Adhesions play a part not just in reproductive medicine, we do not know why some patients form adhesions and other patients do not. There are attempts to inject hyaluronic acid into the cavity after an operation or into the abdominal cavity, liquids, patches. There’s a lot of options, they do not prove to be very effective. Some patients are very resistant to these measures, but since they don’t hurt, surgeons try to use them because they don’t have big side effects or no side effects at all.
Any operation can cause adhesions, the more invasive it is, the more likely you might have them. A normal diagnostic laparoscopy is not very invasive, it’s minimally invasive. If you remove hydrosalpinx, it’s not very invasive and would not cause a lot of adhesions. There are very few therapeutic means to prevent adhesions, injecting hyaluronic acid, putting in some net-like structures. Usually, the minimal invasive laparoscopy with the clipping or resection of the hydrosalpinx is not very invasive and should not cause problems.
Anything that alters the endometrium can contribute to some problems with getting pregnant, so yes, if there are any infections, long-lasting infections, chronic infections, untreated conditions, they can negatively impact fertility. That’s why in the pre-IVF workup, all this is included the HPV test, the pap smear before you start going into this journey. If you’re under 35 and trying to conceive naturally, your doctor would let you try for 12 months to get pregnant if everything checks out fine. If you’re over 35, they would give you 6 months, but they want to know beforehand, yes, infections like that can negatively impact the outcome.
There is some controversy about that, and you’ll find tons of publications where the academics fight about thresholds. What is big in terms of the intramural fibroids, the ones trapped in the wall, you don’t touch them if they do not distort the endometrium. What is big in that context? The threshold is 4 to 5 centimetres, and again you have to consider two things.
If you operate, and it’s very invasive, you leave a scar, scar tissue can again impact implantation, so you have to walk the fine line and decide case by case. The cut-off, I would say, is 5 centimetres. The other fibroids, which are outside, the subserosal fibroids, can be bigger, you don’t care about them if you don’t have symptoms. Those you do not touch, only if they cause symptoms or are big, but the huge ones nowadays are very rare, you don’t see them anymore.
No, it doesn’t affect it because the cavity is unaffected by an outside fibroid. There are discussions about the fact that fibroids cause some metabolical issues, they produce factors that might impair, but that is controversial as well so an outside fab fibroid that does not distort or touch or affect the cavity is not a cause or problem or explanation for miscarriage.
A big chunk of our patients is over 40. First thing in the context of reproduction in nature or IVF, the egg is more important than the sperm cell. The maternal age defines egg quality, egg quality defines embryo quality, so the most important contributing factor for not having had success with two transfers of visually very good embryos, morphologically speaking, good embryos is maternal age. If you imagine you have a 32-year-old patient who has the same embryos, the same classification and let’s say this patient has the same uterus, cavity and the same everything, then from the outside, you don’t see anything. You just know that there’s a 10-year age difference that is the most defining, most impacting factor. Maternal age is something unfortunately, we don’t have treatment for anything that really could improve age, we can’t improve egg quality.
There are some studies to show, but if you look at the context, we know that there are some studies that claim that the usage of DHEA, which is not a drug at least in Germany it’s not considered a drug, it’s like a nutrition supplement that this might increase egg quality, but the studies show not. Some studies say it might increase egg quantity, but there is very little to do in this case. Being 42 or younger, you want to be sure that the uterus cavity is okay, but I suppose your doctors did that, but other than there’s not a lot you can do and that would be a topic for another talk.
Some clinics, especially, in the U.S., would then tell you to do a PGT-A, formally called PGS, which screens for aneuploid embryos. Be very careful there because data shows it’s not the case, and ESHRE, the European Society and the American Society, for the time being, do not recommend aneuploidy screening in advanced maternal age.