Traditionally, the chief causes of RPL have been thought to be due to embryonic chromosomal abnormalities, maternal anatomic abnormalities such as a uterine septum, luteal phase defects, and antiphospholipid antibodies. Other factors such as infection and hypercoagulable state have also been considered but to a somewhat lesser degree.

When to initiate an RPL workup has been a source of recent debate. Classically, conducting a workup for RPL was recommended after three miscarriages. Recent data does not necessarily support this traditional evaluation protocol [18, 19]. The evaluation of healthy women after a single loss is usually not recommended as this a relatively common, sporadic event. However, the risk of another pregnancy loss after two miscarriages is only slightly lower (24–29%) than that of women with three or more spontaneous abortions (31–33%) [10]. Therefore, evaluation and treatment can reasonably be started after two consecutive miscarriages [3, 6, 7, 11]. Furthermore, additional testing such as chromosomal testing of the products of conception from a second miscarriage may confer a cost savings measure [18, 19]. Based on available data, we outline a new strategy for the workup of RPL (◘ Figs. 15.1 and 15.2).

An evaluation of an RPL patient should always include a complete history, including documentation of prior pregnancies, any pathologic tests that were performed on prior miscarriages, any evidence of chronic or acute infections or diseases, any recent physical or emotional trauma, history of cramping or bleeding with a previous miscarriage, any family history of pregnancy loss, and any previous gynecologic surgery or complicating factor. A summary of the diagnosis and management of recurrent pregnancy loss includes an investigation of genetic, endocrinologic, anatomic, immunologic, microbiologic, and iatrogenic causes (◘ Table 15.1).

We outline a proposed algorithm for the evaluation and treatment of RPL (◘ Figs. 15.1 and 15.2). Under this new schema, no diagnostic/therapeutic action is recommended following one miscarriage unless clinically indicated, such as in the case of a submucosal myoma. A fetal karyotype is recommended after the second miscarriage. Products of conception (POC) to send for karyotype may be obtained from early nonviable pregnancies either via traditional D+C. POC may be sent for traditional karyotype or, as we recommend, be sent for 23 chromosome pair microarray evaluation.

The results of this POC karyotype guide further evaluation. If the POC are found to be aneuploid, no further evaluation or treatment is recommended at that juncture because the cause for the loss is known, though all future early miscarriages should also be subject to karyotypic evaluation. If an unbalanced chromosomal translocation or inversion is identified in the fetal POC, then the workup would focus on performing parental karyotypes and offering appropriate therapeutic options such as preimplantation genetic testing. If the fetal POC are found to be chromosomally normal, then a full RPL workup is to be done. If the fetal POC karyotypes have not been performed, then we recommend a full RPL workup after at least two miscarriages. The full RPL workup is outlined in ◘ Fig. 15.1.

What constitutes a full RPL is a topic of debate. We recommend including an anatomic evaluation, endocrinologic evaluation, testing for autoimmune factors, evaluating lifestyle and environmental factors, microbiologic factors and obtaining parental karyotypes if the karyotypic status of prior POC is unknown. Not included in this evaluation are more controversial types of testing and therapies such as those dealing with thrombophilic factors, immunotherapy, and other evaluations though these may be appropriate in certain clinical situations. Below, we describe the physiologic background, diagnostic approaches, and therapy of the various components of our proposed RPL workup. In addition, we will address other more controversial proposed etiologies of RPL.

Congenital malformations of the reproductive tract result from failure to complete bilateral duct elongation, fusion, canalization, or septal resorption of the Müllerian ducts. Müllerian anomalies were found in 8–10% of women with three or more consecutive spontaneous abortions who underwent hysterosalpingography or hysteroscopic examination of their uteri [3, 4, 20]. Inadequate vascularity compromising the developing placenta and reduced intraluminal volume have been theorized as possible mechanisms leading to pregnancy loss.

The most common congenital abnormality associated with pregnancy loss is the septate uterus (◘ Fig. 15.3). The spontaneous abortion rate is high, averaging about 65% of pregnancies in some studies [21]. A septum is primarily composed of fibromuscular tissue that is poorly vascularized. This lack of vascularization may compromise decidual and placental growth. Alternatively, an uterine septum may impair fetal growth as a result of reduced endometrial capacity or a distorted endometrial cavity [21]. Uncontrolled studies suggest that resection of the uterine septum results in higher delivery rates than in women without treatment. Other congenital abnormalities such as uterine didelphys, bicornuate, and unicornuate uterus are more frequently associated with later trimester losses or preterm delivery.

Intrauterine trauma resulting from endometrial curettage or endometritis is associated with a risk for the development of adhesions. Intrauterine adhesions (synechiae) are an acquired uterine defect that has been associated with recurrent miscarriage. The severity of adhesions may range from minimal to complete ablation of the endometrial cavity. The term Asherman’s syndrome is often used to describe intrauterine adhesions associated with oligo or amenorrhea. These adhesions are thought to interfere with the normal placentation and are treated with hysteroscopic resection. The insertion of an intrauterine balloon catheter for one week is recommended after resection of synechiae by some physicians to help prevent reformation of adhesions. During this time antibiotic prophylaxis with doxycycline (100 mg twice a day) is given to prevent endometritis. Patients may also be given estrogen and progestin for 1 month.

Intrauterine cavity abnormalities, such as submucosal leiomyomas and polyps, can contribute to pregnancy loss. Depending on the leiomyoma size and location, it may partially obliterate or alter the contour of the intrauterine cavity, providing a poorly vascularized endometrium for implantation or otherwise compromising placental development. Uterine leiomyomas and polyps may also act like an IUD, causing subacute endometritis (◘ Figs. 15.4 and 15.5). Until recently, it was felt that only submucous leiomyomas should be surgically removed prior to subsequent attempts at pregnancy. However, several recent studies investigating the implantation rate in women undergoing in vitro fertilization have clearly demonstrated decreased implantation with intramural leiomyomas in the range of 30 mm [22]. Minimally invasive surgery is the method of choice to correct the uterine septum as well as to remove fibroids, adhesions, and polyps [23].

Cervical incompetence can be considered as an acquired uterine anomaly that is associated with RPL. The diagnosis of cervical incompetence is based on the presence of painless cervical dilation resulting in the inability of the uterine cervix to retain a pregnancy. Cervical incompetence commonly causes pregnancy loss in the second, rather than first, trimester [24]. It may be associated with congenital uterine abnormalities such as septate or bicornuate uterus. Rarely, it may be congenital following in-utero exposure to Diethylstilbestrol. It is postulated that most cases occur as a result of surgical trauma to the cervix from conization, loop electrosurgical excision procedures, dilation of the cervix during pregnancy termination, or obstetric lacerations .

Maintenance of early pregnancy depends on the production of progesterone by the corpus luteum. Between 7 and 9 weeks of gestation the developing placenta takes over the progesterone production. Luteal phase deficiency (LPD) is defined as an inability of the corpus luteum to secrete progesterone in high enough amounts or for too short a duration. The preponderance of evidence suggests that LPD is a preovulatory event most likely linked to an alteration in the preovulatory estrogen stimulation which may indicate poor oocyte quality and a poorly functioning corpus luteum [26, 27]. Classically, the diagnosis is based upon results of endometrial biopsy, though this is currently not recommended as a diagnostic modality. Most authors advocate the measurement of serum progesterone levels in the luteal phase for the diagnosis of LPD with levels below 10 ng/ml considered abnormal [28]. However, progesterone levels are subject to large fluctuations because of pulsatile release of the LH hormone. Moreover, there is a lack of correlation between serum levels of progesterone and endometrial histology [29]. While conflicting data exist, a recent Cochrane review evaluating 15 trials concluded that there was a benefit to the routine administration of progesterone to all women with a history of RPL [30, 31]. Progesterone is available either as intravaginal suppositories (50–100 mg twice daily starting the third day after LH surge and continuing for 8–10 weeks) or as intramuscular injections (50 mg IM daily).

Untreated hypothyroidism may increase the risk of miscarriage. A study of over 700 patients with recurrent pregnancy loss identified 7.6% with hypothyroidism [32]. Hypothyroidism is easily diagnosed with a sensitive TSH test and patients should be treated to become euthyroid (defined for the purposes of RPL as between 1.0 and 2.5 uIU/mL) before attempting a next pregnancy [1, 6, 30, 33]. The exact value at which to treat subclinical hypothyroidism is somewhat controversial, however, with some professional societies not recommending treatment with TSH levels less than 4 uIU/mL [34]. It has also been suggested that thyroid antibodies are elevated in women with recurrent pregnancy loss. A retrospective study of 700 patients with recurrent pregnancy loss demonstrated that 158 women had antithyroid antibodies but only 23 of those women had clinical hypothyroidism on the basis of an abnormal TSH value [35]. The presence of antithyroid antibodies may imply abnormal T-cell function, and therefore, more of an immune dysfunction rather than an endocrine disorder may be responsible for the pregnancy losses. The Endocrine Society recommends that patients with RPL be treated to keep a TSH level of between 1.0 and 2.5 uIU/mL in the first trimester [33]. For TSH levels found to be between 2.5–10 mIU/mL, a starting levothyroxine dose of at least 50 μg/d is recommended [33].

Patients with poorly controlled diabetes are known to have an increased risk of spontaneous miscarriage, which is reduced to normal spontaneous loss rates when women are euglycemic preconceptually [36]. Testing for fasting insulin and glucose is simple and treatment with insulin-sensitizing agents can reduce the risk of recurrent miscarriage [37]. More recently, determining the average load of blood glucose through testing of hemoglobin A1C has become an increasingly utilized modality to evaluate insulin resistance [6, 7]. Because there is strong evidence that obesity and/or insulin resistance are associated with an increased risk of miscarriage, weight reduction in obese women is a first step in the treatment. Metformin seems to improve pregnancy outcome, but the evidence for this treatment is limited to a few cohort studies. Metformin is a Category B medication in the first trimester of pregnancy and appears to be safe. Other endocrine abnormalities, such as thyroid disorders and diabetes, should be corrected prior to conception.

Normal circulating levels of prolactin may play an important role in maintaining early pregnancy Data from animal studies suggest that elevated prolactin levels may adversely affect corpus luteal function; however, this concept has not been proven in humans [38]. A recent study of 64 hyperprolactinemic women showed that bromocriptine therapy was associated with a higher rate of successful pregnancy and that prolactin levels were significantly higher in women who miscarried [39].

Follicle stimulating hormone (FSH) is thought to be a marker of the number of follicles available for recruitment on any given menstrual cycle. Therefore, elevated levels of FSH in the early follicular phase of the menstrual cycle are representative of diminished ovarian reserve; a condition in which there a low number of follicular units available for recruitment. More recently, other markers, such as decreased anti-Müllerian hormone, have been introduced to identify diminished ovarian reserve. Although the frequency of elevated day 3 FSH levels in women with recurrent miscarriage is similar to the frequency in the infertile population, the prognosis of recurrent miscarriages is worsened with increased day 3 FSH levels [40]. Although no treatment is available, testing may be helpful in women over the age of 35 with recurrent pregnancy loss, and appropriate counseling should follow.

Thrombophilias are thought to be responsible for more than half of maternal venous thromboembolisms in pregnancy, however ACOG recommends that only patients with a personal or family history of thromboembolic events should be tested [60]. The association of inherited and acquired thrombophilias with adverse pregnancy outcome is still being investigated but current evidence suggests a limited role [61]. The recommended evaluations for patients with a personal or strong family history of thrombosis are: