Introduction

Fibroid is the commonest non-cancerous growth of the smooth muscle layer of the uterus.¹ It is also known as leiomyoma and most commonly occurs in women of reproductive age.² They are usually asymptomatic and often detected incidentally during pelvic ultrasound or clinical examination done for other indications and require no treatment or follow-up.^2,3 However, 30% of the patients present with severe symptoms, which decrease their quality of life and require treatment.²

About 10-40% of fibroid cases are associated with various complications, in which recurrent miscarriage or recurrent pregnancy loss (RPL) is one among them.⁴ Recurrent miscarriage is the sudden loss of three or more successive pregnancies in the first trimester with the same biological father.⁵

Uterine fibroids

Aetiology

The causative factors of fibroids are unclear. Genes have been explained as a factor for the occurrence of fibroids. The hormones present naturally in the bodies of those assigned female at birth (AFAB), oestrogen and progesterone, have a significant impact on the growth of fibroids.⁶

Risk factors

Higher risk:

• African descent – fibroids are two to three times more common in black women
• Nulliparity – having never given birth to a live baby
• Family history
• High body mass index (BMI)⁷
• Early menarche⁷
• Early contraceptive use – before the age of 16⁷

Lower risk:

• Multiparity – having given birth more than once ⁷
• Use of progestin-only contraceptives for many years ⁷

Types of uterine fibroid

Based on where they are positioned, uterine fibroids are categorised as:⁶ 

• Subserosal – on the outer surface of the uterus
• Intramural – within the wall
• Submucosal - just beneath the uterine lining
• Cervical – in the cervix
• Intraligamentary – located within the connective tissue adjacent to the uterus 

Impact of fibroid characteristics on pregnancy

Fibroids in pregnancy are linked to the occurrence of miscarriage, with different types of fibroids having different effects. Submucosal, intramural, and subserosal fibroids affect pregnancy in a decreasing order of severity.⁸ Studies suggest that subserosal fibroids do not affect fertility or cause miscarriage. However, both intramural and submucosal fibroids are associated with lower live birth rates and a higher risk of miscarriage. Removal of submucosal fibroids is advised for a better pregnancy outcome.⁹ 

Additionally, the rate of miscarriage is higher in women with multiple fibroids when compared to those with a single fibroid.¹⁰ As the size of the fibroid increases, new blood vessels develop to supply blood to the fibroid, reducing blood supply to the uterus and the growing foetus, hindering foetal growth. Uterine fibroids also cause fetal malformations.¹¹ Fibroids are seen in around 10% of pregnant women, and the chance of fibroids increases with age. Its presence at a young age is linked to family history. Hormones in pregnancy are also directly related to the growth of the fibroid and its impact on pregnancy.¹¹

Fibroids in the body of the uterus are more likely to cause miscarriage than fibroids in the inferior part of the uterus. Increased uterine irritability and contractility lead to miscarriage in pregnancy with fibroids. Fibroids can also compress and disrupt blood flow to the placenta and foetus, especially when the placenta implants near a fibroid.¹¹

Mechanisms linking fibroids to miscarriage

Distortion of the uterine cavity

The shape of the uterine cavity is altered by the presence of submucosal and some intramural fibroids, which negatively affect the pregnancy. The endometrial receptivity, embryo implantation, and pregnancy are impaired by the deformed uterine cavity. It significantly lowers the rate of pregnancy and increases the risk of miscarriage.¹² 

Fibroids disrupt endometrial receptivity by physically altering the uterine architecture, impairing sperm and embryo transport, and interfering with implantation. Excessive extracellular matrix (ECM) production in uterine fibroids leads to increased uterine stiffness, abnormal contractility, and impaired vascular remodelling, contributing to early pregnancy loss.¹²

Placental abnormalities

Placental abnormalities can also present during pregnancy if fibroids coexist. The risk of placental abruption (abruptio placentae) increases three times, especially when the size of the fibroid is more than 200 cm,³ or if the location of the placenta is retroplacental or submucous. Studies reveal that there is double the chance of developing placenta praevia in pregnant individuals with fibroids.¹¹

Effect on endometrial receptivity and implantation

Implantation of the embryo needs a healthy endometrium with receptivity, which depends on molecular events influenced by hormones, growth factors, cytokines and other signalling molecules. Uterine fibroids interfere with the molecular events essential for implantation, leading to improper implantation and early pregnancy loss (miscarriage).¹²

Key factors for endometrial receptivity

HOXA10 and HOXA11, which are HOX genes, are essential for endometrial receptivity, preparing the endometrium for implantation. In women with submucosal fibroids, the expression of HOXA10 is reduced, especially in the area overlying the fibroid, impairing the implantation of the embryo. Removal of the intramural fibroid improves the endometrial expression of HOXA10 and HOXA11 but not the removal of submucosal fibroids.¹²

Cytokines and growth factors

For the implantation of embryos, Leukocyte inhibitory factor (LIF) and IL-11 play an important role. The level of  LIF and IL-11 is lower in women with submucosal fibroids, which may impair implantation.¹²

Immune changes

Macrophages and natural killer (NK) cells are vital for implantation. In women with uterine fibroids, there is a rise in the production of macrophages and a fall in natural killer cells. The imbalance in macrophage and natural killer cell populations disrupts endometrial function, leading to reduced receptivity and impaired implantation.¹²

Growth factors

Growth factors play a crucial role in preparing the endometrium for implantation, particularly through the process of decidualisation. Bone morphogenetic protein 2 (BMP2) is an important growth factor involved in the mechanism. However, submucosal fibroids are associated with resistance to BMP2 signalling, which negatively affects cell growth and differentiation. This results in poor decidualisation and compromised implantation outcomes. Additionally, women with submucosal fibroids present with elevated levels of TGF-β3, which blocks BMP2 signalling and results in impaired embryo implantation. Low BMP2 is also associated with reduced endometrial expression of HOXA10 and LIF. These changes are associated with more miscarriages and lower implantation rates.¹²

Diagnosis

Fibroids are usually diagnosed when patients consult a doctor for complaints such as period pain and heavy bleeding. Uterine fibroid diagnosis involves:⁶

• Gynaecological examination – large fibroids can be identified 
• Ultrasound examination – transvaginal ultrasound scan provides details about the number, size, shape, and position of the fibroid
• MRI scan – suggested based on the findings of prior examinations
  • Helps to determine:⁷
    • The blood supply and degeneration of the fibroid
    • How close the fibroids are to the serosal and mucosal layer of the uterus, and hence useful in determining the treatment
• Complete blood count – If there is concern for anaemia because of heavy bleeding⁷
• Thyroid-stimulating hormone test - To rule out thyroid issues as the cause for heavy bleeding⁷

Treatment

The size, number, and position of the uterine fibroid determine its management. Treatment options include oral medicines, surgical removal, uterine artery embolisation (UAE), and MRI-guided focused ultrasound (MRgFUS). Treatment options include:¹³

• Hormone treatment – hormonal contraceptives to alleviate the heavy bleeding and hormones that prevent the production of oestrogen (GnRH analogues)
• Surgery - to remove the fibroid or entire uterus
• Block/reduce blood flow to the fibroid to reduce its size.
• Focus ultrasound surgery uses waves to heat and destroy the fibroid. 
• NSAIDs (Non-steroidal anti-inflammatory drugs) – to reduce the period pain 

Precautions

• An AFAB individual with a fibroid, and planning for pregnancy, should assess the size and location of any fibroid with a pelvic examination and ultrasound prior to falling pregnant
• A saline infusion sonogram performed before assisted reproduction can help detect submucosal fibroids
• An office hysteroscopy helps to assess the endometrial cavity
• During pregnancy, identifying the position of fibroids in relation to the placenta and cervical canal is important for evaluating the risk of placental complications¹³

Summary

In pregnancy, when uterine fibroids coexist, there is a 10-40 % chance of complications, especially miscarriage. The risk varies according to the location, size, and type of uterine fibroid. Fibroids located within the uterine wall or beneath the lining (intramural and submucosal) are more likely to cause miscarriage and reduce live birth rates than those on the outer surface (subserosal). Having multiple or large fibroids further elevates the risk of miscarriage. The treatment also depends on the characteristics and position of the fibroid.