Fibroids and infertility.

The surgical procedure addressing fibroids must ensure minimal risk to future fertility. Less is more and, ideally, all procedures should aim to avoid complications, such as synechiae for intrauterine surgery, and periuterine and peritubal scarring for open or laparoscopic myomectomy. The use of prophylactic antibiotics and antiadhesion formation barriers is routinely recommended. Antiadhesion formation barriers include gels and absorbable barriers that can be applied at laparotomic and laparoscopic myomectomy. A comparison of different media showed hyaluronic acid‐carboxymethylcellulose film to be highly effective and superior to the other antiadhesion materials (Dextran 40, factor 13 with fibrinogen, control) in preventing uterine adhesions after myomectomy. 29 A recent meta‐analysis showed that a cellulose barrier (mesh or powder) applied on the incision site at laparoscopy significantly reduced subsequent adhesion formation (RR 0.63). 30 Similarly, Cannis et al. 31 observed that a hydrophilic resorbable antiadhesion film (PREVADH) significantly reduced adhesion incidence and severity after laparotomic myomectomy. Gels (auto‐cross‐linked hyaluronic acid) have also been shown to prevent uterine synechiae after hysteroscopic myomectomy. 32 Mechanical barriers such as an inert intrauterine coil can also be used. In an ideal scenario, fibroid surgery for infertile females would be performed by an advanced minimally invasive surgeon who understands the reproductive needs of this group of patients.

All authors contributed to the research, writing, editing, and finalizing of the manuscript.

No funding was received for the planning, research, writing, submission, or publication of this manuscript.

Acknowledging the well‐established regional and ethnic variability, fibroids represent the sole cause of infertility in 2%–3% of women trying to conceive. 7 , 8 The prevalence of fibroids in the population of women with infertility has been reported as 5%–10%. 7 There are many mechanisms by which fibroids affect human fertility, from interference with intercourse to anatomical, functional, immune, and dysbiotic mechanisms. A recent paper suggests seven hypotheses. 7 The clinical presentation of large fibroids, dyspareunia, menorrhagia, and anemia will affect intimate relationships and indirectly result in female infertility. In a multinational study, Zimmerman et al. 8 showed that 42.9% of women reported fibroids negatively affecting their sexual life, with dyspareunia reported by 24% of women with fibroids compared with 9% of women without. In another study, up to 60% of African American women felt that fibroids affected their sex life. 9 The loss of opportunity to conceive due to dyspareunia and anemia should not be neglected when assessing infertile women presenting with a fibroid uterus. Anatomically, fibroids can affect the uterine cavity, fallopian tubes, and oocyte pick‐up mechanism. Fibroids that affect the uterine cavity, located either intracavitary or subserosally, impact endometrial development and endometrial receptivity, resulting in reduced embryo implantation and increased spontaneous pregnancy loss rates. 10 , 11 , 12 Normal peristalsis of the junctional zone is enhanced before ovulation to facilitate gamete transport and decreases to low amplitude waves after ovulation to allow implantation. This pattern appears to be disturbed by uterine fibroids, although the specific fibroid type most responsible remains uncertain. Myomectomy appears to restore normal peristalsis. 13 Furthermore, endometrial blood circulation can be reduced in the presence of a fibroid that undergoes angiogenesis and when fibroids are very large, significant uterine distortion with tissue edema is easily identified at surgery. Other pathophysiological mechanisms include tubal function alterations through obstruction of gamete transport and disruption of ciliary activity, altered immune milieu, and effect of the endometrial‐myometrial junction function. 14 Weak evidence is emerging of a link between a diagnosis of vaginal dysbiosis and uterine fibroid presence. In an observational study, the authors profiled the vaginal and cervical microbiome from 29 women with uterine fibroids and 38 healthy women; a total of 125 samples were obtained and sequenced. 15 They found a disturbance to the regular microbiome in the presence of uterine fibroids and a distinct pattern to the characteristic vaginal and cervical microbiome, with significantly enriched Erysipelatoclostridium , Mucispirillum , and Finegoldia , and depleted Erysipelotrichaceae UCG‐003 and Sporolactobacillus . A recently published pilot study by Korczyńska et al. 16 investigated the microbiota composition in the uterine cavity, cervix, and stool using 16S rRNA bacterial gene sequencing, alongside the concentration of bacterial metabolites in stool samples, comparing women with uterine fibroids to a control group. Lactobacillus iners was found to be overrepresented in cervical swabs from women with uterine fibroids compared to the control group. Furthermore, stool samples from patients with uterine fibroids exhibited higher Shannon‐indexed α‐diversity compared to the control group. The authors suggested that microbiome‐targeted therapies for uterine fibroids and related disorders are an area of future research interest. The presence of fibroids can affect the outcome of pregnancy and this aspect must also be considered when advising infertile women presenting with large fibroids. A recent meta‐analysis showed that women presenting with fibroids in pregnancy have increased rates of pregnancy loss, intrauterine fetal demise, preterm birth, placenta previa, placental abruption, breech presentation, pre‐eclampsia, cesarean delivery, and postpartum hemorrhage. 17 The majority of fibroids in women of reproductive age are asymptomatic and diagnosed only when investigations for infertility are pursued, unless they are palpable abdominally and observed by patients. Fibroid size, location, and proximity to the endometrium will affect the likelihood of conceiving. In the majority of cases, the round well‐defined growth clarifies the diagnosis; however, difficult differentials include adenomyosis, and pedunculated and ovarian fibroids. Clinical examination and ultrasound assessment (transvaginal or abdominal) confirm the diagnosis. An MRI can aid diagnosis and is recommended especially in cases where there is suspicion of malignancy (a fast‐growing fibroid or the presence of pain) or adenomyosis needs to be ruled out. The FIGO subclassification system details eight types of fibroids depending on location in the three uterine wall anatomical layers (Figure  1 ). 18 FIGO subclassification system (PALM‐COEIN) for uterine fibroids, reproduced with permission. 18 To date, the impact of certain types of fibroids on fertility remains a matter of intense debate. In an initial meta‐analysis, Pritts 19 showed that submucosal fibroids are associated with lower clinical pregnancy rates (RR 0.30) and implantation rates (RR 0.28) compared to controls. When women with submucosal fibroids were considered separately, pregnancy was increased after myomectomy compared with infertile controls (RR 1.72) and delivery rates were equivalent to infertile women without fibroids (RR 0.98). An updated meta‐analysis in 2009 offered location‐focused answers: subserosal fibroids do not affect fertility, submucosal fibroids affect fertility, and removal normalizes pregnancy rates and live birth rates. 20 The authors could not provide definitive evidence on the impact of intramural fibroids on fertility. The most recent systematic review 21 specifically addressed the intramural fibroid scenario, showing that intramural fibroids reduce fertility rates and that myomectomy confers no benefit. Women with intramural fibroids smaller than 3 cm had lower clinical pregnancy rates than women without fibroids (OR 0.53, 95% CI, 0.38–0.76) and lower ongoing pregnancy or live birth rates (OR 0.59, 95% CI, 0.41–0.86). Similar findings were seen for women with fibroid sizes between 3 cm and 6 cm (OR 0.43 for clinical pregnancy rates and OR 38 for ongoing pregnancy or live birth rates). Women with fibroids larger than 5 cm had similar pregnancy rates as women without fibroids. The presence of more than one fibroid reduced the clinical pregnancy and ongoing pregnancy or live birth rates, with an OR of 0.62 (95% CI, 0.44–0.86) and 0.57 (95% CI, 0.36–0.88), respectively. In summary, subserosal fibroids do not appear to affect fertility, submucosal fibroids reduce fertility, and both fertility and live birth rates after myomectomy are improved, becoming similar to those of women without fibroids. While intramural fibroids reduce pregnancy and live birth rates, myomectomy does not appear to offer fertility benefit.

Fibroids diagnosed in an infertile patient call for diagnostic, clinical, counseling, and surgical skills above the routine management of fibroids in women who have completed their families. Adequate initial diagnosis and correct counseling allow for a joint decision between the medical provider and the patient as to the best way to help. While not all infertile women with fibroids require an intervention, surgery remains the mainstay for FIGO Type 0, 1, and 2 fibroids as they affect fertility. No definitive answer exists as to the value of surgery for Type 3 fibroids on female reproductive function. Current gaps and opportunities for future research include ethnic and genetic differences in fibroid biology and infertility risk, fibroid characteristics (number, location, size), impact on natural and assisted conception outcomes, randomized controlled trials comparing surgery with no intervention for multiple small intramural subserosal fibroids, and elucidating the molecular mechanisms for fibroid proliferation and spontaneous resorption.

Infertility is defined as the inability to establish a pregnancy after 12 months of regular vaginal intercourse 1 and etiologically can be due to male and female factors, among which is the presence of uterine fibroids. The causal relationship between fibroids and infertility remains complex. It is well established that fibroids are less common in women who have children, thus it is no surprise that the prevalence of fibroids in the infertile population is higher. 2 , 3 Risk factors for uterine fibroids include advancing age, ethnicity, early menarche, low parity, diet, obesity, genetic factors, and caffeine and alcohol intake. 2 , 4 Current demographic trends and in particular the expansion of the reproduction window to the third and fourth decade of life is resulting in a greater burden of fibroids on female infertility due to increased incidence and different growth patterns at different ages. Peddada et al. 5 showed that similar fibroid growth rates exist between black and white women in young age groups (<35 years); however, fibroids grow slower in white women compared to black women in the ≥45 age group. The increased incidence of obesity among women of reproductive age coupled with elevated estrogen levels augment the risk of developing fibroids, while multiparity appears to offer a protective effect. 2 , 4 The increase in unhealthy diets might also contribute to a rise in fibroid prevalence; a diet rich in vegetables and adequate vitamin D levels has been shown to reduce the risk of occurrence. 6 Women diagnosed with infertility are more likely to be diagnosed with fibroids as they are more advanced in age and of lower parity, with the majority being nulliparous. This article is written from the perspective of a consultation with a patient presenting with infertility in which a fibroid has been diagnosed during investigation of the above‐mentioned presentation.

The authors have no conflicts of interest related to the planning, research, writing, and submission of this manuscript.

The clinical intervention will depend upon the assessment of the fibroid uterus but also on the final diagnosis for the couple attending with infertility, contributing factors being semen analysis parameters, female age and weight, ovarian reserve, type of infertility (primary or secondary), and tubal patency. While, in general, fibroids require treatment when they become symptomatic, in the context of infertility, treatment of a fibroid can vary depending on size, proximity to the endometrium, and presenting complaint. As a general rule, the further the fibroid is from the endometrium, and the smaller the size, the less its impact on fertility. From the perspective of the infertile patient, selective progesterone receptor modulator therapy, such as ulipristal acetate, has shown significant reduction in fibroid size via oral therapy over a 6‐month period. 22 However, acute liver failure has been described as an adverse effect, and for this reason ulipristal acetate is now rarely used. Interventional radiology methods include focused ultrasound and uterine artery embolization therapies. High‐intensity focused ultrasound (HIFU) focuses the ultrasound energy on the target lesions, such as uterine fibroids, without affecting the surrounding organs. As regards ovarian reserve, after HIFU therapy, studies have shown no impact 23 , 24 while modest evidence exists on pregnancy outcomes, with pregnancy rates between 7% and 36%. 25 It appears that HIFU ablation is safe for infertile patients receiving therapy. Uterine artery embolization is not recommended in women contemplating a pregnancy due to the risk of premature ovarian insufficiency. 4 A systematic review of fibroid therapy showed that live birth and miscarriage rates following uterine artery embolization were 11.9% and 27.4%, respectively. 26 Radiofrequency ablation has recently emerged as a promising therapy for intramural fibroids due to its ease of use and excellent outcomes in experienced hands. Rey et al. 27 analyzed 226 women who became pregnant after transvaginal radiofrequency ablation and showed the volume reduction of Type 2–5 fibroids to be 49.4% (interquartile range, 26.8%–64.7%) and 69.8% (interquartile range, 45.9%–82.4%) at 6 and 12 months, respectively. Spontaneous conception occurred in 34.5% and in 65.5% after assisted reproduction. Miscarriage rates were 15.9%, with occurrence of premature delivery (before 37 weeks of gestation) in 4.1% and pre‐eclampsia in 4.3%. The authors suggest a 6‐month interval to conception. Expertise on this technique is limited to a few countries. A summary of evidence is presented in Table  1 . Fertility outcomes after radiological intervention for treatment of fibroids. Abbreviations: HIFU, high‐intensity focused ultrasound; UAE, uterine artery embolization; RFA, radiofrequency ablation. UAE is not recommended for women that wish to conceive. Surgery remains the definitive intervention for the treatment of fibroids in women presenting with infertility and includes a vaginal (hysteroscopic) or abdominal (laparoscopic or laparotomic) approach. Prior to surgery, gonadotropin‐releasing hormone agonists (GnRHa) may be used for 2–3 months to reduce the size of a fibroid, especially when a hysteroscopic route is considered. Regarding definitive intervention, we focus on the FIGO classification to decide which fibroids require treatment. We acknowledge that the least invasive procedure when addressing small Type 0, 1, and 2 fibroids is an outpatient hysteroscopy performed under local anesthesia. This procedure is not widely practiced globally, remaining the procedure of choice in experienced centers and for small fibroids (<3 cm). Type 0 and 1 fibroids present with infertility and menorrhagia, and potential anemia. If fibroid size is less than 3 cm, an outpatient myomectomy under local anesthesia remains the intervention of choice, while patients with larger fibroids require GnRHa therapy and electrosurgical approach under general anesthesia. The procedure should be within the remit of skilled hysteroscopic surgeons. Mechanical morcellators, resectoscopes, and laser vaporization can all be used. When the fibroid is located predominantly in the myometrium and considering that sometimes it is not easily visible under a secretory endometrium, the surgical procedure remains challenging even for the expert hysteroscopic surgeon. For larger Type 2 fibroids, GnRHa preparation and sometimes repeat interventions are required. For fibroids over 3 cm and in particular for multiple Type 2 fibroids, an abdominal approach should be considered. Despite that even intramural fibroids can affect implantation, current evidence remains inconclusive regarding treatment of Type 3 and hybrid Type 2–5 fibroids. No strong evidence exists on the optimal approach and most practitioners will propose myomectomy for a fibroid larger than 5 cm, the abdominal route (laparotomy or laparoscopy) being primarily used. A recent meta‐analysis reconfirmed that intramural fibroids less than 6 cm in size have a powerful negative effect on fertility, suggesting that multiple intramural fibroids should be removed as fertility rates are affected. 21 How long to wait after myomectomy before trying to conceive is a question not answered to date. A systematic review on time interval from myomectomy to pregnancy and the complications that occurred in pregnancy was recently published. 28 The authors showed that the mean interval to pregnancy was 18 months and that the risk of uterine rupture was extremely low at 0.4%. As the shortest time from myomectomy to pregnancy was 4.6 months, an interval of 3 months to allow adequate scar healing could be considered when a full wall thickness myomectomy is performed. Special mention is needed for the circumstances where a large fibroid mobilizes the ovary cranially and when an oocyte pick‐up is not technically possible, making myomectomy a necessary procedure.

A summary of recommendations when women presenting with infertility are diagnosed with fibroids is detailed in Table  2 . Table  3 provides guidance related to the need to consider surgical removal. This covers infertile women prior to IVF and infertile women undergoing IVF. Fibroids and infertility: Summary of recommendations. Women with uterine fibroids are not 100% infertile Infertile patients should be provided with information about the impact of fibroids upon fertility, interventions available, intervention risks, and the risks if no intervention takes place Prevalence Possible impact Interventions Risks and benefits Prevalence Possible impact Interventions Risks and benefits All services that provide an infertility clinic should have access to noninvasive and surgical interventions, provided ideally by a team of radiologists and reproductive medicine and surgery specialists Infertile women with fibroids affecting the endometrium should be offered surgery In women who need IVF and where transvaginal access to the ovaries is impaired, a myomectomy should be offered A 3‐month healing period is recommended after abdominal myomectomy Where the full thickness of the uterine wall was breached during myomectomy, consideration for cesarean delivery should be given Fibroids and infertility: Guidance on management according to FIGO classification.