Approach

Evaluation for recurrent miscarriages traditionally starts after the third consecutive miscarriage. However, depending on the discretion of the physician and presence of other factors such as maternal age, investigations can start after 2 miscarriages. Prevalence and frequency of causes found after 2 miscarriages are similar to those found after 3 or more miscarriages.[3]

History

A history is needed to confirm the clinical diagnosis of recurrent miscarriage and to attempt to discover any underlying cause for this condition. It is common to start history-taking with basic demographics such as:

  • Maternal and paternal age

  • Ethnicity

  • Occupation

  • Consanguinity.

Although sensitive, information about paternity of all pregnancies, and whether the partner previously fathered any children in previous relationships, should be established. Thereafter, detailed information about every pregnancy, preferably in chronological order, including miscarriages and live births, is obtained. For all miscarriages, history needs to include:

  • The gestational age at which the miscarriage occurred

  • How the diagnosis of miscarriage was made

  • Findings on ultrasound scan, if it was used

  • Details regarding how the miscarriage was managed

  • Results of any fetal karyotype performed.

Based on the history, miscarriages can be classified into:[54]

  • Biochemical loss (pregnancy confirmed only on serum or urinary hCG)

  • Sac loss (ultrasound scan shows only a gestational sac with minimal embryonic structures)

  • Fetal loss (loss of fetal heart activity that had been previously seen).

Miscarriages can also be classified into:

  • First-trimester miscarriage (early pregnancy loss of <12 weeks' gestation)

  • Second-trimester miscarriage (late pregnancy loss of >12 weeks' gestation).

Any loss after 24 weeks' gestation is termed a stillbirth. This information may help to define possible aetiology and the type of further evaluation required.[54] It is also important to ask whether the patient has been using any treatment for the prevention of recurrent miscarriage.

Similarly, for live births the following information needs to be documented:

  • Gestational age at birth

  • Complications during pregnancy and delivery

  • Mode of delivery

  • Weight of the baby

  • Current condition of the baby.

Gynaecology history should include:

  • Complete menstrual history, including last menstrual period, cycle length, regularity of cycle, and symptoms of intermenstrual bleeding

  • Cervical smear history and any previous treatment for abnormal smears, such as large loop excision of the transformation zone (LLETZ) or cone biopsy

  • Contraceptive history, such as the method, duration of use, and adverse effects (if relevant)

  • History of previous pelvic inflammatory disease

  • History of any infertility treatment (e.g., ovulation induction or assisted conception).

The medical history should particularly include:

  • Inquiry about the presence of autoimmune disease, arthritis, diabetes, thyroid dysfunction, vascular thrombosis, and skin disorders

  • A family history regarding the medical conditions mentioned above

  • A family history of congenital abnormalities, recurrent miscarriage, or pregnancy complications.

The surgical history should focus on:

  • Previous abdominal surgery

  • Cervical surgery (e.g., knife cone biopsy) or uterine surgery (e.g., hysteroscopic septal resection or myomectomy)

  • The number of surgical uterine evacuations performed as the management option for previous miscarriage.

Information on any regular medicine taken and drug allergy should be attained. It is important to ask regarding the use of folic acid and advise daily intake of 400 micrograms if the patient is trying for a pregnancy. Social history should include the smoking status and number of cigarettes smoked a day, amount of alcohol intake, and amount of caffeine consumed.

Physical examination

A general assessment of the patient should be made, including measurement of the BMI. Particular note should be made of any hirsutism or acne (may be signs of polycystic ovarian syndrome). Abdominal palpation is routine to exclude large masses, such as fibroids. A speculum examination is carried out to exclude obvious cervical structural abnormality. Bimanual examination is performed to assess for uterine size and the presence of any adnexal masses.[55]

Laboratory investigation

Recurrent idiopathic miscarriage is the most common type of recurrent miscarriage and is a diagnosis of exclusion when all investigations ordered are normal or have returned negative. Laboratory investigations are the most important investigations for recurrent miscarriage. Results of some of these tests may diagnose a cause for recurrent miscarriage. The rationale for choice of investigations should be evidence-based and focused on the possible causative factors and the treatment available that can improve pregnancy outcome.[9]

Initial blood tests for all patients with recurrent miscarriage could include:

  • FBC

  • Blood group and antibodies

  • Antiphospholipid antibodies (ELISA for IgG and IgM anticardiolipin antibodies; lupus anticoagulant using dilute Russell's viper venom time, kaolin clotting time, or activated partial thromboplastin time; and ELISA for IgG and IgM for beta-2 glycoprotein-1 antibodies).

Although some national guidelines do not recommend routinely screening for thyroid disorders, diabetes, and hyperprolactinaemia in the absence of symptoms, these are easily treatable conditions where there is a potential to improve pregnancy outcome, and thus are commonly requested in many hospitals.

Screening for thrombophilia (factor V Leiden gene mutation, prothrombin G20210A gene mutation, protein S and C assays, activated protein C resistance assay, and antithrombin assay) may identify an associated condition.[9][22][56] The American Society for Reproductive Medicine recommends screening a patient if there is a personal history of venous thromboembolism or if the patient has a first-degree relative with known or suspected thrombophilia; otherwise screening is not recommended.[57]

There is no evidence for routine screening for various autoantibodies (e.g., antinuclear antibody, mitochondrial and smooth muscle antibody) and thyroid antibodies as they have no clear association with recurrent miscarriage and/or there is no recommended treatment available. Similarly, investigations for natural killer cells should not be done unless in the context of a research setting.[58]

It is important to ascertain the karyotype of a miscarried fetus, as the finding of an abnormal karyotype provides for a better prognosis in a future pregnancy and reassures the patient that this is more than likely to be a random event. Cytogenetic analysis of a second miscarriage is often recommended before performing other tests, because if the products of conception are abnormal, further work-up is not required as the miscarriage is due to abnormal karyotype. This strategy is often used in older women as the incidence of aneuploidy is greater in these women.[59][60] Chromosomal microarray analysis has been found to be associated with an increased rate of detecting chromosomal abnormalities compared with karyotyping; however, some of these abnormalities are variants of uncertain significance.[61]

Another cytogenetic investigation would be the karyotype of both partners to exclude balanced Robertsonian translocation. Although the knowledge of this problem may allow for genetic counselling, it does not necessarily change the management plan, as active intervention would involve in-vitro fertilisation (IVF) with or without preimplantation genetic diagnosis to replace only chromosomally normal embryos, which has proven not to improve live-birth rates.[62][63][64] Furthermore, these couples have encouraging pregnancy outcomes of 70% live birth rates in the subsequent pregnancy. Thus, routine parental karyotyping for chromosomal abnormalities is not recommended and should be offered only when karyotype of the products of conception shows an unbalanced structural chromosomal abnormality.[9]

It is not necessary or beneficial to universally perform a high vaginal swab on every patient with recurrent miscarriage to detect vaginal infections, including bacterial vaginosis, unless they present with symptoms of a pelvic infection or have a history of second-trimester miscarriage.[43][65] This is because patients with second-trimester miscarriages screened and treated for bacterial vaginosis in early pregnancy may have a reduced risk for another late miscarriage or preterm birth.[65]

Imaging and surgical investigations

Guidelines recommend that a 2D pelvic ultrasound scan, either transabdominally or transvaginally, be arranged for all patients as part of the initial investigations, to exclude obvious congenital uterine malformations and for assessing the morphology of both ovaries.[9] However, the evidence for treatment and outcome for both uterine malformations and polycystic ovarian syndrome in the next pregnancy remain inconclusive, and patients need to be aware of this before having an ultrasound scan.

Hysterosalpingography was previously accepted as the diagnostic tool for investigating the uterine cavity. However, it is uncomfortable, it exposes the patient to radiation, it carries risks of contrast allergy, and it can exacerbate pelvic inflammatory disease. Thus, it is no longer commonly used as a screening tool for uterine abnormalities.[66]

Sonohysterography or saline-infused sonography is another imaging technique used to outline the interior uterine contour. Although this is less painful and more accurate than hysterosalpingography in diagnosing uterine malformations, it is still invasive, and this service is not widely available.[66]

The advancement and use of 3D ultrasonography looks promising, as it is non-invasive and offers both accurate diagnosis and classification of congenital uterine anomalies. Furthermore, it is highly reproducible and not operator-dependent, as volume is generated by automatic sweep of the mechanical transducer. This may remove the consideration for any surgical investigations such as hysteroscopy or diagnostic laparoscopy.[66] However, at present 3D scanning in gynaecology is not yet universally available, as these machines are expensive, and training needs to be provided first.

In a patient with second-trimester miscarriages, or a history suggestive of cervical incompetence, transvaginal ultrasound scan can be performed in the second trimester and serially thereafter to measure the cervical length, as this predicts risk of preterm birth.[67] In a non-pregnant state, measurement of the cervical length has not been proven useful for predicting outcome in a subsequent pregnancy. A cervical length of more than 25 mm in second trimester of pregnancy is associated with a reduced risk of preterm delivery.[67]

Surgical investigations (hysteroscopy or diagnostic laparoscopy) are usually considered only if previously mentioned investigations are normal. Even so, they are not commonly carried out unless there is a specific indication. Hysteroscopy is now performed only when there is uncertainty about the diagnosis of a uterine anomaly. Therapeutic measures may be carried out simultaneously, such as removal of endometrial polyps, endometrial adhesiolysis, and correction of uterine anomalies.[17][18] Similarly, diagnostic laparoscopy was traditionally used to diagnose bicornuate uterus, but with advancements in ultrasonography, it is rarely carried out now for this indication.

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