Test
Aim
Performed
Uterine assessment
2D Ult rasound
Myometrium, endometrium, ovaries, pelvis
RPL + infertility
3D Ultrasound
Uterine cavity (congenital anomalies), myometrium, endometrium
RPL + infertility
Hysteroscopy
Uterine cavity, myomas, endometrium (Ashreman syndrome)
RPL + infertility
Hysterosalpingography
Uterine cavity
Infertility
Laparoscopy
Endometriosis, tubal potency
Infertility
Fallopian tubes assessment
Hysterosalpingography
Fallopian tubes potency
Infertility
3D ultrasound
Hydrosalpyx
RPL + infertility
Endocrine assessment
Thyroid function, prolactin
Ovulation dysfunction, implantation failure
RPL + infertility
Diabetes mellitus screening
Glucose intolerance, hyperandrogenemia
RPL + infertility
Male evaluation
Basic semen analysis
Sperm count and basic function
Infertility
Advanced semen analysis
DNA fragmentation, sperm immunoglobulin, reactive oxygen species and antioxidants capacity
RPL + infertility
Ovaries
FSH, antral follicular count or AMH
Ovarian reserve assessment
Infertility
Genetic
Karyotype of the couple
Translocations, deletions
RPL
Karyotype and micro-deletions of the m ale
Assessment of azoospermia
Infertility
Autoantibodies and immune function
Anti-cardiolipin antibody and lupus anticoagulant
Autoimmune disorders
RPL
Congenital Uterine Anomalies
Congenital uterine anomalies, also known as Mullerian anomalies are the result of an incomplete fusion of the mesonephric ducts [10]. The prevalence of the Mullerian anomaly is debatable as a result of the imprecision of the commonly used diagnostic methods and the lack of widely accepted standard classification. Moreover, since many of the Mullerian anomaly cases are asymptomatic [11], the true prevalence of the anomaly in the general population is difficult to determine [12]. The commonly cited prevalence of uterine anomalies observed in the fertile population is 3.2 % [11]. Reviewing five different studies of almost 3000 cases, Grimbizis et al. [13] reported an overall incidence of 4.3 % indicating it is relatively common.
The etiology of the congenital uterine anomalies remains unclear with the exception of maternal exposure to diethylstilbestrol (DES) [14].
The Mullerian anomalies are classified according to the severity of the anomaly, the clinical manifestation, treatment, and prognosis. Regrettably, there is no commonly acknowledged classification system for the Mullerian anomalies. The American Fertility Society classification was published on 1988 [15]. In this system the anomalies are classified from type I representing Müllerian agenesis or hypoplasia through type VI representing DES-related anomalies with all the range of anomalies in-between. Likewise, the European Society of Human Reproduction and Embryology (ESHRE) and the European Society for Gynaecological Endoscopy (ESGE) issued in 2013 their classification system [16] ranging from class U0 as the normal uterus to class U5 as the aplastic uterus.
The association between both the congenital and acquired uterine anomalies was reviewed thoroughly in Chap. 7. As concluded there, both congenital and acquired uterine structural anomalies of the uterus play a major role in the pathophysiology of RPL. The diagnostic modality will be a 2D followed by 3D trans-vaginal ultrasonography with a diagnosis rate of more than 95 % of the cases.
The association between congenital uterine anomalies and infertility is less established, creating a debate regarding the approach to uterine anomalies in infertile patients. Several studies suggested that uterine anomalies distort the uterine cavity and as a result increase infertility rates [13, 17, 18], cause RPL [14, 18] and impose perinatal risk of preterm labor amongst other obstetric complications [19, 20] while other studies claim that uterine anomalies cause trouble in maintaining the pregnancy but not in the actual conception [14, 21, 22]. However, accumulating evidence including recent data indicates that resection of a uterine septum may be beneficial in cases of inf ertile patients [23–25].
Leiomyoma
Uterine leiomyomas, also known as leiomyomatas or fibroids, are benign solid tumors of the uterus. They are usually slow-growing and asymptomatic. Myomas are common in woman of reproductive age with prevalence as high as 70–80 % in woman aged 50 years [26]. The myomas differ in their symptoms according to their anatomic location, specifically in the uterine sub-serosa, intra-myometria or sub-mucous layers. Myomas have been previously reported to be associated with break-through uterine bleeding and symptoms caused by the enlarged uterus imposing on neighboring organs, such as the urinary bladder or the bowel.
Beside the symptoms discussed above, uterine leiomyomas were also reported to be associated with RPL and infertility. Myomas, especially sub-mucous myomas, may distort the endometrial cavity, negatively impacting the implantation of the embryo. Although the mechanism by which the myomas impact implantation is not completely understood, it is estimated that atrophy of the endometrium overlaying the myoma is the cause for the implantation failure [27]. A systemic review reported a significantly higher rate of pregnancy losses in women with sub-mucous myomas [28]. While atrophic endometrium may cause implantation failure, the distorted shape of the uterus was suggested to alter the gametes and embryo transport through blockage of the tubal ostia, decreasing chance of fertilization and implantation [29, 30].
Myomas altering reproduction can be surgically removed. The surgical approach is determined by the location and size of the myoma. Sub-mucosal myomas can be hysteroscopically removed while intra-mural and sub-serosal myomas can be laparoscopically approached. The impact of the removal on reproduction, however, is still debatable. While the sub-serosal myomas probably do not impact reproduction considerably, their removal questionably improves reproductive outcome [31]. However, in cases of sub-mucosal myomas and intra-mural myomas, which alter the uterine cavity, surgical resection of the myomas may improve reproduction scores both for infertility and RPL. The same applies to cases of unexplained i nfertility in the presence of myoma in which myomectomy appears to be beneficial [31–34].
Male Factor
The male factor is a well-established and an obvious cause of infertility. Male factor includes not only the sperm production and function but also other factors such as erectile dysfunction, anatomic alterations like hypospadias or micro-penis, endocrine disorders, and others. It was commonly believed that if fertilization did occur, the inability of the fetus to undergo a successful implantation or to maintain the pregnancy was associated with only female factors.
The association between basic semen parameters and RPL is still widely debated [35]. As more advanced tests for male factor were developed, especially in male DNA structures and their impact on the embryonic development, this association changed.
Accumulating evidence supports the link between male factors and RPL. Several studies reported a positive association between paternal age and the risk of RPL [36, 37]. Chromosomal aberrations in the sperm are associated with embryonic developmental arrest or implantation failure and consequently, early pregnancy loss [38]. Male factors are now known to play a key role in fertilization, implantation, embryo development and placental development [39, 40].
The association between male DNA dysfunction and RPL supports the notion that regular work-up should not exclude male factor as an etiology of RPL. Hence, the discovered positive association between sperm dysfunction and RPL led some of the researchers to recommend routine advanced male factor assessment in cases of RPL even in the pre sence of a normal male infertility basic workup [38].
Endocrine Factors
Polycystic Ovary Syndrome (PCOS), diabetes mellitus, hyperprolactinemia, luteal phase defect, and thyroid antibodies and disease are commonly encountered endocrine factors in cases of both RPL and infertility. Although the exact pathophysiology underlying these disorders in relation to RPL and infertility still remains elusive, experts have determined commonly accepted mechanisms of action. Together, these five disorders serve to establish the endocrinological connection between women with RPL and infertility in terms of shared mechanisms, diagnosis, treatment, and prognosis.
Diabetes Mellitus
There are two types of diabetes mellitus: Type 1 diabetes (T1D) and Type 2 diabetes (T2D). T1D is a disorder in which the body cannot produce sufficient insulin. The more prevalent T2D occurs via the onset of insulin resistance and can be caused by high-fat diets and sedentary lifestyles [41]. Adequate insulin production or supplementation is necessary for the maintenance of a healthy female reproductive system [42]. Females with uncontrolled T1D usually experience delayed menarche [42]. They may also be exposed to acute or chronic hyperglycemia, which has damaging effects on the embryo, particularly via intracellular glucose starvation.
Insulin resistance in T2D patients leads to hyperinsulinemia and can result in ovulatory dysfunction, hyperandrogenism, and infertility [42]. One mechanism in which hyperinsulinemia affects the reproductive hormonal axis is by reducing sex hormone-binding globulin (SHBG). Decreased SHBG activity is coupled with an increase in circulating testosterone levels. This can lead to anovulation because high testosterone levels can suppress FSH [43]. T2D also elevates the glucose production in the liver and increases insulin resistance from other tissue. Because the embryo is sensitive to insulin, inadequate glucose consumption due to hyperinsulinemia and hyperglycemia can lead to apoptosis, increasing the risk of miscarriage [41].
Many women with T2D are also obese and studies have indicated that obese patients usually take longer to conceive and have poorer blastocyst quality [43]. Women with diabetes who also had low BMI displayed high HbA1c levels and had menstrual irregularities [43]. Studies have shown that high HbA1c levels in diabetic pregnant women indicate poor pregnancy outcomes and increased miscarriage rates.
Thus, uncontrolled diabetes mellitus is considered a risk factor for both RPL and infertility primarily because of its association wit h hyperinsulinemia, hyperglycemia, and obesity and high HbA1c levels.
Polycystic Ovary Syndrome
Polycystic Ovary Syndrome (PCOS) is considered the most common endocrine abnormality , affecting 5–10 % of women of reproductive age [44, 45]. The Rotterdam Criteria for diagnosing PCOS has to fulfill at least two out of the three following criteria: oligo/anovulation, hyperandrogenism, and presence of polycystic ovaries. Women with PCOS display elevated levels of LH and thereby have an increased androgen production in theca cells. Hyperandrogenism can then cause increases in estrone levels, which suppresses FSH production, leading to ovarian dysfunction , oligo/amenorrhea, anovulation, and subsequently, infertility. The prevalence of PCOS in women with RPL is as high as 56 %. Obesity and supraphysiological levels of LH can impair ovarian folliculogenesis and increase risk of miscarriage. Studies have further implicated an association between PCOS and hyperinsulinemia/insulin resistance, obesity, and hyperhomocysteinemia. Hyperinsulinemia and insulin resistance are shown to negatively affect pre-implantation, by decreasing the activity of proteins involved in feto-maternal adhesion. Hyperhomocysteinemia may also have adverse effects on embryo quality. These factors are considered the link between women with PCOS and RPL/infertility [46].
Thyroid Antibodies and Disease
The two main thyroid disorders are hypothyroidism and hyperthyroidism. Hyperthyroidism does not display significant connections to RPL or infertility. Hypothyroidism, primarily caused by Hashimoto’s disease, however, affects 2–4 % of women of reproductive age and is associated with miscarriage, preeclampsia, and preterm birth [47]. Hypothyroidism can either be classified as overt (clinical) or subclinical, both of which can increase risk of first trimester loss and infertility. Subclinical hypothyroidism is more common and can directly lead to anovulation and increases in prolactin levels [48]. Women with hypothyroidism display high levels of thyroid-regulating hormone (TRH). TRH activates thyroid-stimulating hormone (TSH) and subsequently the main thyroid hormones, T3 and T4. TRH, additionally, causes idiopathic increases in prolactin levels, which in turn causes dysregulation of hypothalamic hormonal function and ovulatory dysfunction. Amenorrhea in hypothyroidism is linked to hyperprolactinemia, which causes a defect in estrogen to LH positive-feedback mechanism and also suppresses LH and FSH. Even in the absence of hyperprolactinemia, hypothyroidism can result in infertility because adequate thyroid activity is needed for greatest production of estradiol and progesterone [49]. Thyroid antibodies are usually higher in women with RPL and impact trophoblast survival and invasion. They can also cause dysregulation of inflammatory processes (i.e., pregnancy), which can lead to greater risk of miscarriage [50]. Overall thyroid antibodies and hypothyroidism are important common factors affecting women with RPL and infertile women.
Hyperprolactinemia
Hyperprolactinemia is a disorder, in which, there is an abnormally high level of prolactin in the bloodstream. Studies have shown that some of the women who have miscarried and/or considered RPL patients display high prolactin levels [51]. One study suggested that high concentrations of prolactin can inhibit progesterone secretion, leading to luteal insufficiency and resulting in infertility. Hyperprolactinemia can also cause hypothalamic dysfunction, defective ovulation and follicle activity, and reduced fecundability, indicative of miscarriage [51]. A possible mechanism for hyperprolactinemia is via dopamine suppression. As prolactin levels increase, dopamine suppresses prolactin production, but indirectly affects GnRH neurons, resulting in hypogonadotropic hypogonadism and possible anovulation. In another study with mice, an alternative mechanism was proposed. Hyperprolactinemia lowered levels of kisspeptin, a protein that stimulates GnRH secretion [52]. Both mechanisms show the same underlying result: hyperprolactinemia affects the hypothalamic-pituitary-ovarian axis, commonly affecting fertility and pregnancy outcomes.
Luteal Phase Defect
Luteal phase defect (LPD) or insufficiency is characterized by insufficient progesterone production and/or progesterone receptivity [53]. Normally, the corpus luteum produces adequate levels of progesterone to prepare the endometrium for blastocyst implantation, favor Th2 cytokines, which are supportive of pregnancy, with progesterone-induced blocking factor, and inhibit prostaglandins, which initiate uterine contractions, to create a stable environment for implantation. Studies have shown that women with luteal insufficiency can have poor luteal blood flow as well as lower FSH and LH signaling, which is vital for adequate folliculogenesis, oocyte maturation, ovulation, and implantation [54, 55]. LPD can engender anovulation, luteal atrophy, or implantation failure in the first trimester, becoming a potential caus e of both infertility and recurrent pregnancy loss in premenopausal women.
Personal Habits
Personal habits such as smoking, alcohol consumption, intense exercise, and substance abuse can negatively impact the female reproductive health and function. Although the exact pathophysiology of these factors is unclear, there are many reports suggesting that these lifestyle choices are potential risk factors for infertility and RPL by causing oxidative stress (OS), hormonal disruption, or physical changes in the female reproductive system.
Smoking
Because of its prevalence, especially in women of reproductive age, cigarette smoking is one of the most clinically relevant risk factors [56]. Cigarette smoke (CS) contains over 4000 chemicals, many of which are known reproductive toxicants [57]. Smoking can lead to many hormonal changes. Research shows that CS causes increased FSH production, shortening the follicular phase and resulting in anovulation, poor luteal function, and menstrual irregularities [58]. Alkaloids present in CS can similarly decrease the production of progesterone, leading to luteal deficiency [59]. CS can also decrease estrogen levels by interfering with granulosa cells and aromatase enzyme, consequently disturbing the pituitary-gonadal axis. One study showed that women who smoked had a significantly increased risk of spontaneous abortion [60].
Harmful chemicals in smoking such as nicotine and polycyclic aromatic hydrocarbons can increase OS in the body by upregulating production of free radicals and/or decreasing antioxidant defenses [57, 61, 62]. Since OS is widely recognized to impair vital processes such as folliculogenesis, steroidogenesis, embryo transport, and uterine receptivity, CS can be highly detrimental to reproductive function. Thus, CS, via OS and ho rmonal alterations, can result in infertility and high risk pregnancies [63].
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