Fibroids and Infertility

Mohamed T

Published on: 2024-02-14

Abstract

Fibroids or leiomyomas are extremely common and are said to be the most frequent benign tumor of the female genital tract. The clinical manifestations vary from abnormal uterine bleeding to causing pain and pressure symptoms and sometimes even urinary symptoms.

Fibroids may also cause pregnancy related problems including infertility, recurrent miscarriage, and other obstetric complications.

Approximately 5-10% of infertile women will have associated fibroids and it may be the only cause of infertility in about 1-2.4% of women [1]. The association between fibroids and infertility is undeniable; however, it is difficult to prove a direct causal relationship and hence this has been a subject of debate for many years.

To date there are also many conflicting studies related to fibroids and infertility, the effects of fibroids and the correct management thereof with regards to improving fertility.

Hence, from the review of the current and past literature there are several factors that one must consider when dealing with an infertile patient with fibroids.

Keywords

Pregnancy Infertility Uterine fibroids

Background

Fibroids are extremely common and are said to be the most frequent benign tumor of the female genital tract. It is said that up to 70% of women will develop fibroids by the age of fifty years [2]. There is an increased incidence with increasing age and fibroids are associated with significant morbidity [2].

Fibroids are a significant economic health burden and treatment costs the state and medical aids millions each year. It is reported that more than one third of all hysterectomies done each year are for fibroid indications [3].

Clinical manifestations vary from abnormal uterine bleeding to causing pain and pressure symptoms and sometimes even urinary symptoms.

Fibroids may also cause pregnancy related problems including infertility, recurrent miscarriage, and other obstetric complications. However, in 30-40% of women, they may be completely asymptomatic [4].

There are many risk factors identified for the development of fibroids. These being race, age, early menarche, parity, caffeine and alcohol consumption, genetic factors and Vitamin D deficiency [2,5].

Race is an important risk factor in the development of leiomyomas. Whilst uterine fibroids affect a large proportion of the population, the prevalence, symptom severity and disease burden are generally higher in African women which is likely due to environmental and genetic factors [2]. Whilst studies have shown that Caucasian women under the age of thirty-five had faster growing tumors than Caucasian women over the age of forty-five years old, women of African origin did not show any decrease in the growth rates with age [2].

Women are at higher risk for development of uterine fibroids if pregnancy is delayed till the third decade of life. Early menarche is usually defined as menarche before the age of twelve years and is considered a risk factor for developing fibroids as well as other hormonal diseases such as breast cancer.

Pregnancy has been found to have a protective effect on the development of uterine fibroids. It has been suggested that during post-partum uterine remodelling, small lesions may be subject to selective apoptosis and fibroid tissue may be highly susceptible to ischemia during uterine remodelling.

Studies have shown that the consumption of caffeine and alcohol increases the risk of developing uterine fibroids in African women.

Another risk factor for developing uterine fibroids is a positive family history, and although the specific genetic components are not fully understood, recent data has suggested that specific subgroups of genetic alterations are correlated with an increased risk for uterine fibroids [2,3].

Vitamin D deficiency also plays an important role in fibroid development and may be a preventable risk factor [5].

Fibroids and Infertility

Approximately 5-10% of infertile women will have associated fibroids and it may be the only cause of infertility in about 1-2.4% of women [1].

The association between fibroids and infertility is undeniable; however, it is difficult to prove a direct causal relationship and hence this has been a subject of debate for many years [6].

The reasons for this are because it is well known that with increased age, there is an increased incidence of fibroids [7,8] and there is also an increased incidence of infertility with increased age [9,10].

There is a current trend of delayed childbearing and therefore the infertile population of women presenting for fertility assistance are mostly those of increased age which makes it difficult to confer this causal relationship and other factors such as diminished ovarian reserve and egg quality all come into play.

Furthermore, fibroids are associated with conditions such as endometriosis and adenomyosis which are also causes of infertility.

All fibroids are heterogeneous in nature and different fibroids impact fertility differently [11,12]. Fibroids can affect fertility in two ways:

By impairing fertilisation and
By affecting implantation

The mechanisms by which fibroids may affect fertilisation is either by anatomic distortion of the cervix and hence impaired sperm entry or by altered uterine contractility which may hinder sperm motility and movement through the uterine cavity and the fallopian tubes.

Mechanical obstruction of the tubal ostia may further impair the entry of sperm into the fallopian tubes.

Even with successful fertilization, fibroids can affect implantation by the following mechanisms:

Altered endometrial development, especially if submucosally located
Through distortion of the cavity
By impaired endometrial blood flow
By impaired endometrial contractility and receptivity

A lot of research has been conducted looking at endometrial receptivity and what genes and growth factors may affect this.

Genes which appear to be most associated with successful implantation is the HOXA 10 and HOXA 11 and women with deficient expression of these genes have reduced implantation rates. Fibroids have been shown to decrease the expression of these HOX genes and hence impairs endometrial receptivity [13]. Munro et al showed that submucosal fibroids may influence endometrial receptivity via transforming growth factor beta 3.

The production of transforming growth factor beta 3 is increased as the size of the fibroid increases and this impairs the endometrial receptivity. Hence the size and the location of fibroids are important [11].

With regards to uterine contractility, it is said that fibroids may affect calcium metabolism by causing a decrease or a defect in calcium extrusion and thus raising the intracellular calcium. This increased intracellular calcium produces myometrial irritability and hyperactivity which results in disruption of the rhythmical contraction process of the Junctional Zone [14].

Effect Of Fibroids On Pregnancy

Early in the first trimester, fibroids cause increased uterine contractility which may contribute to miscarriage, and in later gestation they may cause mechanical effects which could result in malpresentation and preterm birth. There is also an increased incidence of placenta previa, placenta abruption and caesarean delivery with fibroids. At delivery there’s an increased risk of atony due to over distension of the uterus and hence risk of post-partum hemorrhage [15].

Figure 1:

Figure 2:

A 2022 publication shows these relative risks for each specific outcome from various studies to date (Figure 1, 2) [15].

Fibroids and the Effect on IVF (In Vitro Fertilisation) outcomes

Most studies regarding fibroids and infertility have in fact been on the IVF (In vitro fertilisation) population and IVF provides a good model to assess the effect of fibroids on implantation by excluding other factors like sperm movement, embryo transport and tubal factors.

Studies have shown that pregnancy rates with IVF depends on the location of fibroids with submucosal being the most detrimental, and subserosal having the least effect [16].

Donnez and Jadoul showed in their 2002 study that there was no difference in implantation and pregnancy rates unless the uterine cavity itself was distorted by myomas [17].

Sunkara et al showed that cavity distorting intramural fibroids adversely affects pregnancy outcomes in women undergoing IVF [18], and several authors recommend their surgical removal.

Pritts et al also showed in his meta-analysis in 2009 the detrimental effect of submucosal fibroids on fertility outcomes [19].

Hence the submucosal fibroids and the cavity distorting fibroids were shown to unquestionably affect fertility outcomes with IVF and there is still no question regarding this point today.

However, the effect of non-cavity-distorting uterine fibroids is still an ongoing debate. Fibroids in other locations, namely types 3, 4, 5, 6, and the 2–5 according to the FIGO (The International Federation of Gynecology and Obstetrics) classification continue to present a clinical conundrum.

Figure 3: [20]

Some experts have proposed that type 4 fibroids should be further classified into type 4a and type 4b. Type 4a if it disrupts the Junctional zone and type 4b if it does not [21].

The conundrum is that some studies showed that intramural fibroids negatively affect IVF outcomes [22,23], and some showed that it did not [24,25]. The most recent studies show that intramural fibroids do indeed have an impact on IVF outcomes even those that are non-cavity distorting.

One of the plausible mechanisms proposed for how intramural fibroids, not distorting the cavity, affects pregnancy is by possibly disrupting the Junctional Zone within the myometrial layer at the initial stages of embryo invasion and placentation [26].

The Junctional Zone Myometrium is a functionally important entity in reproduction for the following reasons.

It is ontogenetically related to endometrium.
It plays a role in gamete transport and implantation.
It undergoes early changes from the time of implantation.
It is involved in decidualisation and trophoblast invasion.

Defective transformation of the Junctional Zone spiral arteries has also been implicated in a spectrum of pregnancy complications like pre-eclampsia for example [27].

Sunkara et al conducted a meta-analysis in 2010 which comprised of nineteen studies and 6087 IVF cycles. The studies had intramural fibroids which ranged from 0.4- 8cm and they were all non-cavity distorting [18].

She also concluded from this meta-analysis that the presence of non-cavity-distorting intramural fibroids is associated with adverse pregnancy outcomes in women undergoing IVF treatment.

Somigliana et al in quick response to the Sunkara’s study published just one year later conducted a small prospective study of 119 patients and an equal number of controls. They concluded that in IVF patients with fibroids less than 5cm and if non-cavity distorting, there was no impact on the success of IVF [28].

The latest meta-analysis published in Fertility and Sterility 2023 included five studies in the final analysis [29].

They showed that women with <6 cm non-cavity distorting intramural fibroids had significantly lower live birth rates (LBRs) compared to women with no fibroids. A significant reduction in LBRs was noted in < 4cm fibroid subgroup but not in the <2 cm subgroups.

Hence in conclusion fibroids of 2–6 cm in size were associated with significantly lower LBRs.

They also noted that owing to a lack of studies, the impact of the number of non-cavity distorting intramural fibroids (single vs. multiple) on IVF outcomes could not be assessed. They further concluded that myomectomy might be offered in clinical practice to women with such fibroids before undergoing IVF treatment.

As for FIGO grade 3 fibroids, which are intra-mural but are abutting the endometrial cavity, there are two recent studies; a retrospective cohort study published in 2018 [30] and a 2023 systematic review and meta-analysis [31], which both show a detrimental effect of such fibroids on IVF outcomes.

Importantly however, the effect of surgery for these FIGO 3 fibroids on IVF outcomes is still not known and more studies are still warranted.

Surgery itself comes with various risks especially blood loss and adhesion formation. Myomectomy is said to be one of the most adhesiogenic procedures. Even when meticulous surgical techniques are adhered to, it can still result in adhesions which can also impact negatively on fertility. Hence it is important to know when to operate and when not to operate.

Donnez and Dolmans in a review article on hormonal therapy for fibroids poses a pertinent question regarding medical therapy.

It states that ‘‘If the negative effect is related to myoma size and proximity of the uterine cavity, why not try a medical approach to reduce the size of the myoma, and to push it back deeper into the myometrium [32]?’’

Conclusion

To date there are many conflicting studies related to fibroids and infertility, the effects of fibroids and management thereof with regards to improving fertility. Recommendations are varied and will likely continue to change as newer studies are conducted and published.

However from review of the past and current literature, it is evident that the following remains important and one needs to consider this when dealing with an infertile patient with fibroids in order to counsel the patient and to manage appropriately.

The site and the size of fibroids is important. Fibroids distorting the cavity clearly impact on fertility. For submucosal and cavity distorting fibroids, surgery is widely accepted to improve outcomes. For the larger 2-6cm non cavity distorting intramural fibroids there is an effect on IVF outcomes and surgery can be considered but one can also consider medical therapy to shrink them and move them further away from the cavity and Junctional Zone.
The number of fibroids is important however there is a paucity of new studies regarding this.
The distance of the fibroid from the endometrium for non-cavity distorting intramural fibroids may impact on fertility. A small study from the Middle East showed that fibroids less than 5mm from the endometrium further reduced pregnancy outcomes but was not found to be statistically significant [33] and newer studies investigating this which also considers fibroid size and number are needed.

International Journal of Womens Health and Gynecology

Fibroids and Infertility

Abstract

Keywords

Background

Fibroids and Infertility

Effect Of Fibroids On Pregnancy

Conclusion

References