Keywords

FormalPara Key Points

  • Most miscarriages are sporadic, and thought to be associated with genetic causes, influenced by maternal age.

  • More than 50% of recurrent pregnancy loss will not have a clearly defined cause after thorough evaluation.

  • Most women with unexplained recurrent pregnancy loss will have successful outcomes in subsequent pregnancies.

15. Case Vignette

A 33-year-old G2P0 woman presents with her partner of 2 years for a consultation for recurrent pregnancy loss. She has been trying to conceive with her partner for 2 years and has experienced two first trimester miscarriages, which were both managed surgically with dilation and curettage (D&C). She reports she has always had her pregnancies confirmed on ultrasound on an early dating scan at 6 weeks with subsequent foetal loss before 12 weeks on repeat ultrasound. Genetic evaluation was not performed on products of conception from either of these pregnancies.

She has a known history of polycystic ovarian syndrome but is otherwise medically well with no other significant medical history. Her only surgeries were her two D&C procedures. She has no gynaecological history and reports regular menses every 28 days with no heavy menstrual bleeding or dysmenorrhoea and onset of menarche at age 13. She reports normal and up-to-date cervical screening tests and denies a history of sexually transmitted infections. She has been taking regular antenatal vitamins and has no known allergies.

Her husband is medically well with no significant medical or surgical history. They both deny the use of alcohol, tobacco or substance use.

15.1 Definition

The definition of recurrent pregnancy loss (RPL) has traditionally included only couples with three or more spontaneous, consecutive miscarriages. Professional organisations such as the American Society for Reproductive Medicine (ASRM) and European Society of Human Reproduction and Embryology (ESHRE) have now redefined RPL as the loss of two or more clinically recognised pregnancies, excluding molar and ectopic pregnancies [1, 2]. However, the previous definition of three or more consecutive pregnancy losses remains in use by other organisations such as the Royal College of Obstetricians and Gynaecologists (RCOG) in the UK, as well as the French College of Gynaecologists and Obstetricians [4, 5]. As the revised definition of recurrent miscarriage is used across more countries and regions, more women and couples will be able to access services for investigation and management. For most investigations, the decision on when to start investigations will need to be decided in a shared decision-making process between couples and their physician [6].

15.2 Evaluation and Treatment

15.2.1 Introduction

The following chapter will review a general approach to investigation and management of recurrent pregnancy loss. A detailed description of potential contributing factors to RPL will follow, as well as the appropriate diagnostic and therapeutic strategies. An initial evaluation for early pregnancy loss is included in ◘ Fig. 15.1, followed by a summary overview of standard workup for RPL in ◘ Table 15.1.

Fig. 15.1
figure 1

Initial evaluation of pregnancy loss. (Adapted from Edition 3)

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Table 15.1 Investigations and management of RPL
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Factors generally accepted to be associated with RPL include embryonic chromosomal abnormalities, uterine malformations, endocrine dysfunction, autoimmune disorders and acquired thrombophilia such as antiphospholipid syndrome [4, 7, 8]. Other causes have been proposed but remain controversial, including chronic endometritis, infectious diseases, inherited thrombophilia, luteal phase deficiency and high sperm DNA fragmentation levels [1, 4, 7].

Investigations for RPL were traditionally only initiated after three consecutive miscarriages. However, recent data does not support this protocol. Several recent studies showed that women with two or three pregnancy losses had similar obstetric characteristics and investigation results with two RPL and three RPL had very similar obstetric characteristics and associated causative factors. Hence, couples with two pregnancy losses should be offered the same care pathway [11,12,10].

Over the years, evidence-based treatments such as surgical management of uterine anomalies and aspirin and heparin for antiphospholipid syndrome have improved outcomes for couples with RPL. However, more than 50% of cases of recurrent miscarriage will not have a clearly defined aetiology [7]. Most investigations and treatment also remain controversial, with a lack of consensus amongst international groups regarding standard investigations and treatment options for RPL [11]. Nevertheless, standard investigations for recurrent miscarriage continue to be important in evaluating potential factors responsible for pregnancy loss [12].

A standard initial evaluation of RPL should include a complete patient history including medical, obstetric and family history, as well as lifestyle factors such as smoking, alcohol consumption and exercise. Medical and family history could be used to tailor diagnostic investigations in RPL. Any previous investigations on prior miscarriages should be reviewed, as well as any evidence of acute or chronic disease.

15.3 Epidemiological Risk Factors

15.3.1 Age

Advanced maternal age is a well-established risk factor for subfertility, foetal anomalies, stillbirth and obstetric complications. Fecundity decreases gradually beginning from 32 years and more rapidly from 37 years, reflecting a decline in the number and quality of remaining oocytes. This progressive atresia of oocytes is associated with elevated levels of follicle-stimulating hormone and anti-Mullerian hormone [13]. Furthermore, age-related decline in fertility is also accompanied by significant increases in rates of aneuploidy and spontaneous miscarriage [4, 7]. Advanced paternal age has also been identified as a risk factor for pregnancy loss, with the highest combined risk seen in couples where the woman is 35 years or older and the man is 40 years or older [14, 15].

15.3.2 Previous Reproductive History

The risk of further miscarriages increases after each successive pregnancy loss, reaching 40% after three consecutive pregnancy losses. A previous live birth does not prevent a woman from experiencing RPL, and the prognosis worsens with increasing maternal age [16, 17].

15.4 Anatomic Risk Factors

Anatomic defects are found in up to 15% of women with RPL and may be classified as congenital malformations or acquired anomalies including intrauterine adhesions, myomas and endometrial polyps. They are thought to interrupt endometrial vasculature and prompt abnormal placentation [1, 2, 4].

15.4.1 Congenital Malformations

Congenital malformations of the reproductive tract result from failure of development, fusion and degeneration of the paramesonephric ducts. Congenital uterine malformations have a well-established association with recurrent pregnancy loss, in addition to other complications such as preterm birth, foetal malpresentation and increased rates of Caesarean delivery [18, 19]. Congenital uterine abnormalities may have varying degrees of symptomatology but can be broadly classified into unification defects (unicornuate, bicornuate or didelphys uterus) and/or canalisation defects from incomplete resorption of the midline septum (subseptate or septate uterus) [20].

Imaging for the detection of uterine malformations is commonly performed via hysterosalpingography but now may be more fully characterised by sonohysterography, laparoscopy, magnetic resonance imaging or ultrasound imaging (two-dimensional or three-dimensional) [21]. Sonohysterography uses the introduction of saline or contrast fluid into the uterine cavity to enhance ultrasound imaging studies and has higher sensitivity and specificity compared to hysterosalpingography or diagnostic hysteroscopy in diagnosis of uterine malformations, with ◘ Fig. 15.2 demonstrating a hysteroscopic approach. In contrast, hysterosalpingography has a good sensitivity for diagnosing more pronounced uterine malformations, but it is limited in differentiating between the types of malformations [22, 23].

Fig. 15.2
figure 2

Uterine septum at hysteroscopy

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There is still insufficient evidence on the efficacy and safety of surgical interventions for improving reproductive outcomes. Some reports have shown hysteroscopic metroplasty for women with septal divisions to reduce miscarriages and improve live birth rates [27,28,26], whilst other studies show surgical management of fusion or unification defects to be of limited benefit [27]. The primary limitation to this data is the lack of large randomised controlled therapeutic trials. An international randomised controlled trial found no evidence that hysteroscopic septum resection improved live birth rates in women with a septate uterus, as compared with expectant management. However, this was limited by a small sample size of 80 women [28]. Until such a study can robustly prove an improvement in reproductive outcomes, patients should be adequately counselled regarding the potential risks of surgery, such as uterine perforation, and participate in a shared decision-making process for ongoing management.

15.4.2 Intrauterine Adhesions

Intrauterine adhesions , or synechiae, occur in sites where the endometrial basal layer has been destroyed, most frequently from curettage, uterine surgery or infection. Endometrial trauma may cause minimal or significant interruption to vasculature, resulting in menstrual abnormalities, infertility and recurrent pregnancy loss. Asherman syndrome describes the presence of intrauterine adhesions with oligo- or amenorrhoea [29].

Hysteroscopic adhesiolysis is now the treatment of choice due to its minimally invasive nature and being able to be performed under direct vision. It does carry significant risks of uterine perforation, and dense scar tissue and difficult entry into the cervix may necessitate laparoscopic or ultrasound guidance, ultrasonography or laparoscopic guidance [30]. Some studies have reported on the use of a Foley catheter introduced into the uterine cavity with an inflated balloon for several days after lysis of adhesions to prevent recurrence. However, this has the added risk of infection and patient discomfort, as well as potential disadvantages of reducing blood flow to the regenerating uterine walls. There is no current consensus regarding surgical method, instruments and any barriers to prevent recurrence and hormonal treatment for endometrial regeneration [34,35,33].

15.4.3 Intrauterine Masses

Intrauterine masses such as endometrial polyps (as seen in ◘ Fig. 15.3) and myomas (in ◘ Fig. 15.4) are postulated to have space-occupying effect that impedes embryonic implantation and potential acts as a foreign body causing subacute endometritis, hence causing pregnancy loss. However, they are also benign growth, which may be present in up to 30–40% of the normal population, and their effect on reproductive outcomes is controversial. There is no evidence for surgical management to improve fertility outcomes [37,38,36].

Fig. 15.3
figure 3

Endometrial polyp at hysteroscopy

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Fig. 15.4
figure 4

Submucosal uterine myoma on saline infusion sonogram

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15.4.4 Cervical Incompetence

Cervical incompetence is a clinical diagnosis, based on a history of late miscarriage preceded by spontaneous rupture of membranes or painless cervical dilation. It is frequently cited as a cause of RPL, more commonly occurring in mid-trimester. However, there are no objective investigations that can identify non-pregnant women with underlying cervical incompetency [37]. It is thought to arise from previous surgical trauma such as cone biopsies, large loop excision of the transformational zone, repeated dilation and curettage or obstetric lacerations. A rarer cause is exposure to diethylstilbestrol (DES) whilst in utero. A Cochrane review identified no conclusive evidence that prophylactic cervical cerclage reduces the risk of recurrent mid-trimester miscarriage. Hence the benefits of serial cervical length measurements and the prophylactic cervical cerclage may be questionable [38].

15.5 Genetic Factors

Over 50% of spontaneous miscarriages are the result of chromosomal abnormalities, which may be of parental origin, or arise de novo in the embryo from parents with normal chromosomes [39]. The most common genetic errors include aneuploidy (gain or loss of a chromosome), chromosomal imbalances (from translocations, inversions, deletions or duplications) and single gene mutations.

15.5.1 Cytogenetic Abnormalities

Embryonic aneuploidies are the most common cause of early pregnancy loss, with up to 90% of chromosomally abnormal embryos spontaneously aborted, as a natural selection mechanism [2, 4, 39]. The most common abnormalities are numeric chromosome errors such as trisomy (60%), polyploidy (20%) and monosomy X (20%). The autosomal trisomies typically arise de novo owing to meiotic nondisjunction during gametogenesis and are associated with increase in age. The parental karyotypes are normal in most of these cases conferring a minimal recurrence risk [40, 41].

15.5.2 Parental Chromosomal Disorders

Most miscarriages occur in chromosomally normal parents. Abnormal parental karyotypes such as translocations, inversions and rarely ring chromosomes are found in around 2–5% of individuals referred for genetic testing after RPL [42, 43].

Balanced translocations are the most common chromosomal abnormalities contributing to RPL. They occur where there is an exchange of chromosome segments and can be categorised as reciprocal or Robertsonian translocations. Robertsonian translocations occur where the two acrocentric chromosomes (numbers 13, 14, 15, 21, 22) are combined near the centromere, with loss of the short arms [44]. Balanced translocations include an exchange of chromosome segments with no loss in the two non-homologous chromosomes. The risk of miscarriage is influenced by the chromosome involved, the size and type of rearrangement as well as the genetic content of the rearranged chromosomal segments. Notably, parents carrying balanced translocations are usually asymptomatic [42, 43].

Rarer chromosomal abnormalities include inversions and ring chromosomes. Inversions occur where a piece of chromosome breaks at two points and reinserts within the same chromosome. Paracentric and pericentric inversions are much rarer but are also associated with an increased risk of RPL. Ring chromosomes occur when two breaks are created in one chromosome and the resulting ends fuse to form a ring [45, 46].

15.5.3 Genetic Evaluation in RPL

If no foetal product of conception histopathology is available from previous pregnancy losses, then parental karyotyping may be considered after an individual risk assessment [1, 2, 4]. However, routine screening of parental karyotyping is not recommended. In couples with no other cause of RPL other than a structural chromosomal rearrangement, nearly two-thirds are likely to have a normal outcome in subsequent pregnancy [42, 47, 48].

Genetic counselling is crucial when a structural genetic factor is identified, as strategies to prevent recurrence will depend on the underlying cause of pregnancy loss. Reproductive options may include preimplantation genetic diagnosis and antenatal genetic diagnosis such as chorionic villus sampling and amniocentesis . This allows for foetal karyotyping to be performed followed by more specific genetic testing such as gene sequencing, polymerase chain reactions (PCR) and restriction fragment length polymorphism (RFLP). Preimplantation genetic diagnosis (PGD) with embryo transfer allows for the transfer of only unaffected foetuses or for the use of donor gametes [49,50,48].

15.6 Endocrine Risk Factors

15.6.1 Luteal Phase Deficiency

Progesterone is necessary for the maintenance of early pregnancy and is initially produced by the corpus luteum, until the developing placenta takes over production between 7 and 9 weeks of gestation. Luteal phase deficiency was first described in 1949, and its defining characteristic is a deficiency in endogenous progesterone, hence affecting normal embryo implantation and maintenance of early pregnancy [49]. Luteal phase insufficiency can be caused by endocrinopathies such as stress, PCOS and prolactin disorders [50].

Although luteal phase deficiency is known to be associated with RPL, finding consistent, accessible and reliable diagnostic criteria for luteal phase deficiency has been challenging, and there remains no consensus regarding its definition [51]. Classically, serum progesterone levels below 10 ng/ml have been associated with an increased risk of miscarriage. However, serum progesterone levels are subject to high levels of fluctuations due to the pulsatile release of luteinising hormone. Traditionally, serial endometrial biopsies would be performed for diagnosis; however, this is not recommended currently for diagnosis, as there is poor reproducibility of findings and high interobserver variation with histological diagnoses [53,54,52].

Progesterone use has been found to be of limited benefit in an unselected population with sporadic miscarriages; however, there is a potential benefit in a subpopulation with three or more consecutive miscarriages [53, 54].

15.6.2 Polycystic Ovarian Syndrome (PCOS)

PCOS is a complex disorder involving abnormalities within the hypothalamic-pituitary-ovarian axis, to cause anovulatory dysfunction, hyperandrogenism and polycystic ovarian morphology. Women may have oligo- or amenorrhoea, obesity and laboratory evidence of elevated androgens, elevated levels of luteinising hormone (LH), insulin resistance and hyperinsulinemia [50]. PCOS is associated with several complications of pregnancy including gestational diabetes, hypertensive disorders including pre-eclampsia and early pregnancy loss. Several of the abnormalities seen in PCOS patients have been independently associated with RPL, including insulin resistance, hyperinsulinemia, hyperandrogenemia and obesity. However, there is a lack of clear evidence that PCOS predisposes to recurrent pregnancy loss, as available studies have not used the Rotterdam criteria to define PCOS, but rather have only used polycystic ovarian morphology [55, 56]. Furthermore, current research indicates that metformin does not reduce risk of pregnancy loss in PCOS , and there is limited evidence to suggest that clomiphene citrate or ovarian drilling is beneficial in this population [56, 57].

There is a need for a reappraisal of available evidence to determine the true prevalence and the role of PCOS in recurrent pregnancy loss.

15.6.3 Thyroid Dysfunction

Thyroid function may vary significantly during normal pregnancy. If overall thyroid homeostasis is to be maintained, the thyroid gland is challenged to increase thyroid hormone production. A study of thyroid function and pregnancy outcome revealed a positive linear relationship between miscarriage and maternal thyroid-stimulating hormone (TSH) levels [58]. Thyroid disorders, especially hypothyroidism and increased thyroid peroxidase antibodies, are correlated with disturbed folliculogenesis, spermatogenesis, fertilisation and embryogenesis and have long been associated with RPL, preterm birth, low birth weight and detrimental effects with foetal neurocognitive development [59, 60].

15.6.3.1 Hypothyroidism

The most common cause of hypothyroidism in pregnant women, affecting nearly 0.5% of patients, is chronic autoimmune (Hashimoto) thyroiditis, followed by endemic iodine deficiency through poor supplementation, poor radioactive iodine therapy and post-thyroidectomy state [60].

Whilst overt hypothyroidism is associated with an increased rate of pregnancy loss, the association between subclinical hypothyroidism (SCH) and miscarriage is less clear. SCH refers to elevated TSH levels with preserved free thyroxine levels [60, 61]. Hypothyroidism may be easily diagnosed with a serum thyroid-stimulating hormone level; however, the threshold level for diagnosing subclinical hypothyroidism is contentious. It is controversial whether to lower the upper limit of normal TSH from 4–5mIU/L to 2.5mIU/L, which represents two standard deviations above the euthyroid population [61, 62]. However, studies which utilised the pre-pregnancy TSH threshold of 2.5mIUL/L found no association with increased pregnancy loss and no improvement with thyroxine replacement therapy [65,66,67,68,66].

There is fair evidence that subclinical hypothyroidism when defined as TSH > 4 mIU/L during pregnancy is associated with miscarriage and routine screening with TSH levels should be offered in RPL [63].

15.6.3.2 Thyroid Autoimmunity

The presence of anti-thyroid antibodies may imply abnormal T-cell function, suggesting an additional immune-mediated role in causing pregnancy loss. For women with thyroid antibodies and a serum TSH 2–4mIU/L, treatment should be considered in early pregnancy [67].

Selenium is postulated to play a key role in thyroid homeostasis through integration into thyroid enzymes responsive for protection against immune-mediated oxidative damage. There have been several studies suggesting selenium treatment to reduce antibody levels, which may allow for lower doses or thyroxine supplementation in women with Hashimoto’s thyroiditis. Unfortunately, there are no current randomised controlled trials to support this treatment in RPL [68].

15.6.3.3 Hyperthyroidism

Hyperthyroidism, found in 0.1–0.4% of pregnancies, is not a known causative factor of RPL. Nevertheless, it is noted that women with untreated overt hyperthyroidism are at high risk of thyroid storm, congestive heart failure, pre-eclampsia, preterm birth and spontaneous miscarriage [69, 70].

15.6.4 Management of Thyroid Dysfunction in RPL

In conclusion, screening with TSH and thyroid autoantibodies and treatment of subclinical hypothyroidism are recommended in women with RPL. Thyroxine administration, commencing at a low dose such as 50 microg daily, is a safe and effective method in reducing early pregnancy loss in women with overt hypothyroidism or in euthyroid women with anti-thyroid antibodies. Current recommendations support thyroxine administration for TSH >4 mIU/L but not at TSH of 2.5–4 mIU/L in the absence of thyroid antibodies [63, 71].

15.6.5 Abnormal Glucose Metabolism

Pregestational diabetes complicates around 1% of pregnancies, and many studies have shown patients with poorly controlled diabetes are known to have an elevated risk of spontaneous miscarriage, preterm birth and hypertensive disorders. The main underlying cause of miscarriage is thought to be lethal embryonic malformations due to glucose teratogenicity if the patient has poorly controlled diabetes in the periconceptional period [72, 73]. Current evidence suggests that well-controlled diabetes is not a risk factor for RPL and that optimal metabolic control for diabetic women is crucial in the periconceptional period and first trimester [1, 4]. Metformin is known to be a safe, effective and low-risk oral hypoglycaemic agent for management of diabetes [73].

15.6.6 Hyperprolactinaemia

Prolactin is commonly measured because elevated prolactin levels are associated with ovulatory dysfunction. The underlying mechanism is unclear, but prolactin is postulated to maintain corpus luteum function and progesterone secretion, although the mechanism is still unclear [74]. Normalisation of prolactin levels in RPL population, with a dopamine agonist such as bromocriptine, was effective in preventing miscarriages but showed no significant difference in conception and live birth rates [75]. Due to the absence of consistent evidence on its association with RPL, prolactin testing is not routinely recommended in the absence of symptoms of hyperprolactinaemia such as oligo- or amenorrhoea [1].

15.6.7 Diminished Ovarian Reserve

Diminished ovarian reserve (DOR) , defined as reduced ovarian reserve markers with regular menstrual cycles, has been suggested to be a causative or prognostic factor in RPL. Ovarian reserve can be assessed with measurements of FSH, oestrogen (E2), inhibin B and anti-Mullerian hormone (AMH) or ultrasound investigation to determine antral follicle count (AFC) and ovarian volume [1, 2, 3].

DOR may be seen following pelvic surgery, chemotherapy and radiotherapy but also conversely in the general population of young women conceiving naturally and is not necessarily considered as a pathological entity. Additionally, ovarian aging may lead to increased rates in foetal aneuploidy, which makes investigation into a direct causative effect with RPL difficult [76, 77]. A recent systematic review and meta-analysis has found an apparent association between DOR and RPL as measured by low AMH levels and AFC [78]. However, more studies are required to evaluate their prognostic value in RPL, and assessment of ovarian reserve is not recommended as part of routine screening [1, 2, 4, 5].

15.7 Immunological Factors

The immune system of pregnant women is tightly controlled to defend against microbial infections and to accept an embryo or the foetus, and inflammation-like processes are crucial for tissue growth, remodelling and differentiation of the decidua during pregnancy. A failure in normal immune control mechanisms may result in an autoimmune response to a developing foetus, like those that develop after rejected grafts in organ transplantation [79]. Autoantibody formation against phospholipids, thyroid antigens and nuclear antigens has been investigated as a potential causative factor in RPL, and 20% of women with RPL will have increased serum levels of autoantibodies, most commonly antiphospholipid antibodies [80].

There is currently insufficient evidence to recommend immune testing such as human leukocyte antigen (HLA) determination, cytokine levels and natural killer cell analyses [81]. Antinuclear antibodies (ANA) will be detected in 10–15% of women, with no clear relationship with pregnancy outcomes. However, some studies have shown a weak association between ANA and RPL, and there is evidence that the presence of ANA may confer a poorer prognosis [82, 83]. Overall, there is no evidence that available immunotherapies such as intravenous immunoglobulins, paternal cell immunisation or donor leukocytes provide any benefit for improving live birth rates. Hence, no immunological tests are recommended as part of routine RPL workup [84].

15.8 Thrombophilia

15.8.1 Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is the only proven thrombophilia associated with recurrent pregnancy loss, with international consensus diagnostic criteria outlined in ◘ Table 15.2 [85]. Between 15 and 20% of women with RPL have positive antiphospholipid antibodies, with the three most clinically recognised and relevant antibodies including lupus anticoagulant (LA), anticardiolipin antibody and anti-beta-2 glycoprotein I which contribute to the laboratory diagnosis of APS. It has been suggested that the presence of anti-beta-2 glycoprotein may indicate an increased risk of thrombosis [86, 87].

Table 15.2 International consensus classification criteria for antiphospholipid syndrome (APS) , which is diagnosed with one of the following clinical and one of the following laboratory criteria are met
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The diagnosis of antiphospholipid syndrome can be complex and is based on a combination of clinical manifestations of vascular thrombosis or pregnancy morbidity, as well as the presence of autoantibodies, on two tests performed 12 or more weeks apart [85]. The hypothesis behind APS and recurrent miscarriage is the encouragement of a hypercoagulable state, inflammatory processes and defective angiogenesis. This is corroborated by the presence of microthrombi within placental vasculature and decidua in pregnancy samples of women with RPL [87, 88].

Standard treatment for APS includes a combination of low-dose aspirin and low-dose heparin, which may reduce pregnancy loss by 54% [89]. Aspirin may be commenced in the periconceptual period, whilst heparin should be commenced after the first positive pregnancy test, with both continued until delivery [90]. The use of prednisolone increases risks of hypertensive disorders, gestational diabetes and preterm birth and is not recommended for treatment of APS [91]. Postpartum thromboprophylaxis is considered for a short interval, and women with known APS should consider avoiding oestrogen containing oral contraceptives due to the persistent thrombotic risk [89, 90].

15.8.2 Hereditary Thrombophilia

Hereditary thrombophilia predisposing patients to venous thromboembolisms include Factor V Leiden mutation, prothrombin mutation, protein C, protein S and antithrombin deficiency. The prevalence of hereditary thrombophilia in women with RPL is unclear, and there is no clear association between RPL and hereditary thrombophilia [92]. Current guidelines recommend screening only in the presence of additional risk factors , such as a positive family history of thrombophilia or a personal history of VTE [93]. Where possible, this should occur 6 weeks following a pregnancy loss or thrombotic event and whilst not on anticoagulants, with suggested testing methods outlined in ◘ Table 15.3.

Table 15.3 Inherited thrombophilia testing
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15.9 Infection

Ureaplasma urealyticum, Mycoplasma hominis, chlamydia, Listeria monocytogenes, Toxoplasma gondii, rubella, cytomegalovirus, herpes virus and other less frequent pathogens have been identified more frequently in vaginal and cervical cultures and serum from women with sporadic miscarriages [94]. Similarly, chronic endometritis has been linked to RPL, as small studies showed an increased prevalence in this subpopulation [95]. However, there remains uncertainty regarding the true impact of chronic endometritis on reproductive outcomes, and there is no consensus on treatment options, coupled with the need for an endometrial biopsy to confirm resolution. Overall, there is no convincing evidence that infections cause RPL, and hence there is a limited benefit of routine screening and antibiotic prophylaxis [96].

15.10 Environmental and Psychological Factors

15.10.1 Lifestyle Factors

Smoking is strongly associated with adverse obstetric outcomes such as miscarriage, stillbirth, ectopic pregnancy, placenta praevia as well as poor neonatal outcomes including preterm birth, foetal growth restrictions and congenital abnormalities. It is thought that cigarette smoking causes adverse trophoblastic function and hence is linked to sporadic pregnancy loss [97].

Other lifestyle factors such as alcohol consumption (3–5 drinks per week) and caffeine consumption (more than three cups of coffee) have been associated with the risk of miscarriage in a dose-dependent manner. However, current evidence is insufficient to confirm this association [98].

15.10.2 Obesity

Obesity represents a major public health challenge worldwide, as it poses a high disease burden and mortality, affecting not only general health but also in the periconceptual period. It is associated with poor reproductive outcomes, including miscarriages, congenital malformations, gestational diabetes, pre-eclampsia, higher rates of Caesarean delivery, thromboembolic events and postpartum infection [99, 100]. A recent systematic review found higher rates of pregnancy loss in obese women with a history of RPL, but not in women who were overweight [101].

15.10.3 Psychological Factors

Recurrent pregnancy loss can have significant emotional impacts on couples, with feelings of loss of and grief intensified with repeated losses [102]. Several reports have tried to find a possible psychological aetiology for RPL, but such associations are inherently difficult to prove, due to the presence of various confounding factors and variables. International societies recommend offering supportive care in dedicated miscarriage clinics for couples with RPL [1, 4].

15.11 Unexplained Pregnancy Loss

Therapeutic interventions should be targeted to the cause of RPL. However, after a thorough evaluation, almost half of the patients will remain without a definite diagnosis. In this subpopulation with unexplained RPL with early pregnancy bleeding, progestogen supplementation may reduce the risk of miscarriage and increase live birth rates in subsequent pregnancies [54, 103].

15.12 Future Pregnancy Outcomes

Pregnancy loss can be an extremely traumatic event for couples, with feelings of helplessness, desperation and despair compounded with subsequent pregnancy losses. These symptoms may also be exacerbated by unnecessary tests that fail to enhance reproductive outcomes [104]. In this way, it is imperative that clinical and diagnostic tests focus on minimising the risk of future miscarriages, optimising the time required to become pregnant again and optimising the chances of live birth. Thankfully, women with unexplained recurrent first trimester miscarriage have an excellent pregnancy outcome if offered supportive care and conceive a subsequent pregnancy with 50–60% success rate [4].

15.13 ReviewQuestions

  1. 1.

    Spontaneous pregnancy loss is most commonly due to:

    1. A.

      Uterine malformations

    2. B.

      Lifestyle factors

    3. C.

      Endocrine dysfunction

    4. D.

      Genetic abnormalities

  2. 2.

    What is the most common anatomic defect associated with recurrent pregnancy loss?

    1. A.

      Leiomyomas

    2. B.

      Bicornuate uterus

    3. C.

      Endometrial polyps

    4. D.

      Uterine synechiae

  3. 3.

    Which of the following is not a diagnostic criterion for antiphospholipid syndrome?

    1. A.

      Antithrombin antibody

    2. B.

      Anticardiolipin antibody

    3. C.

      Lupus anticoagulant

    4. D.

      Anti-beta-2 glycoprotein antibody

15.14 Answer

  1. 1.

    D

  2. 2.

    B

  3. 3.

    A