Recurrent pregnancy loss (RPL) is spontaneous loss of two or more pregnancies before 20 weeks of gestation, excluding molar or ectopic pregnancy. Pregnancy confirmed by urinary or blood human chorionic gonadotropin (HCG) is sufficient [1]. Documentation by ultrasonography or histopathology is not required, as access to early pregnancy sonography is variable across the patient population [2]. Biochemical pregnancy inclusion is supported, as it has a similar impact as that of clinical loss [1]. About 2% of pregnant women have 2 consecutive pregnancy losses; hence, RPL requires evaluation and management [2]. Due to a lack of clear etiology in approximately 50% of patients, RPL is complex and challenging. In those with unclear etiology, RPL creates anxiety/dissatisfaction among patients and frustration among treating physicians, thereby attempting unproven therapies. Patients with RPL are more likely to have health issues later in life; hence, complete evaluation of maternal and paternal health is essential. Counseling about the natural history of RPL is important, as 50–80% of patients will succeed in subsequent pregnancy attempts without any intervention [1].

RPL are of two types: Primary is pregnancy loss in a woman who has never given birth to any live infant, and Secondary is pregnancy loss in a woman who had a previous live birth. [3, 4]

Genetic: 50–60% of first-trimester miscarriages are due to embryonic aneuploidy. Sporadic aneuploidy is strongly correlated to maternal age, with around 50% in age < 35 years and 70% with age > 40 years. [1] Aneuploidy has a limited role in second/third trimester losses. Patients with RPL has more chance of having euploid miscarriages, and the likelihood increases with an increase in the number of miscarriages.

Anatomic: Uterine anomalies can be primary like septum, bi/unicornuate uterus or acquired like submucous fibroid, polyp, IU adhesions and cervical incompetence.

Endocrine factors include luteal phase defect (LPD), thyroid disease, diabetes mellitus, polyendocrine metabolic ovarian syndrome (PMOS), and hyperprolactinemia. RPL is associated with overt and subclinical hypothyroidism and thyroid autoimmunity (TPO antibodies). For diabetes, risk factors include overweight, gestational diabetes mellitus (GDM), family history, PMOS, age > 40 years. Hyperprolactinemia is associated with ovulatory dysfunction and luteal phase defect.

Antiphospholipid antibody syndrome (APLS) is an acquired thrombophilia, which is associated with recurrent pregnancy loss.

Immunological: Inherited thrombophilia is of importance only when a positive family or personal history of venous thrombosis is present. Autoimmune disorders like Systemic Lupus Erythematosus (SLE) cause recurrent abortion through immune-mediated placental damage and inflammation. The presence of antiphospholipid antibodies (found in one third of patients) causes microthrombus in the placenta.(Fig. 1).

Infection: Chronic endometritis is a subclinical inflammatory or infective process with the presence of plasma cells in functioning endometrium. The diagnostic criteria may be difficult if associated with IU pathologies like polyp, retained products of conception (RPOC), and fibroid. Chronic infection in an immunocompromised patient could be challenging.

Ovarian reserve evaluation (AMH levels) is not of much value; however, younger patients with decreased ovarian reserve have some evidence of potential high risk of RPL. [1]

Environmental: Cigarette smoking, excessive coffee/alcohol consumption, recreational drug users, and obesity could be possible predisposing factors for RPL.

Male factor: Elevated sperm DNA fragmentation (SDF) is associated with miscarriage. Environmental toxins, pollutants, drugs, febrile illness, cigarette smoking, and varicocele increase in paternal age are responsible factors.

History should include details of gestational age, treatment given during previous pregnancy loss, and all etiological factors. Thorough clinical general and pelvic examination should be done (Table 1).

Endocrine factors: TSH, Free T4, for subclinical hypothyroidism, TPO antibodies for thyroid autoimmunity are advisable. In First trimester: TSH 2.5 m IU/L, Second/Third Trimester: TSH 3 m IU/L with free T4 in normal range are desirable. Blood sugars with HbA1c for diabetes, fasting insulin levels for PMOS, and prolactin levels are recommended.

Parental karyotyping is recommended only after individual risk assessment, detection of unbalanced structural chromosomal abnormalities in products of conception, or no chromosomal testing of miscarriage is done.

Uterine cavity assessment: Various noninvasive to minimally invasive procedures from TVS, HSG, sonohysterography (SHG), 3D USG, MRI, hysteroscopy, and laparoscopy are available. Each diagnostic technique has its advantages and disadvantages and can be used in combination to make an accurate evaluation. 3D sonography has the highest accuracy rate (97.6%) followed by SHG (96.5%), 2D USG (86.6%), and HSG (86.9%) [1]. MRI is more than 90% accurate in diagnosing uterine anomalies, with an added advantage of diagnosing urinary tract anomalies that often coexist. The high-cost factor does not make it a first-line diagnostic modality.

Antiphospholipid antibody syndrome (APLS): The diagnosis requires the presence of circulating antiphospholipid antibodies in plasma on more than one occasion 12 weeks apart. The test is recommended in those with three or more miscarriages or with a single miscarriage after 10 weeks of pregnancy (after the presence of cardiac activity), unexplained prior VTE, pregnancy complications like preterm, PE, placental insufficiency. Lupus anticoagulant (LAC), anticardiolipin (aCL), IgG and IgM (Immunoglobulin), anti-beta 2 glycoprotein-I (aB2GPI) IgG and IgM antibodies should be included. Titres more than the 99th percentile or IgG > 40 units are considered positive and persistently positive in repeat test after 12 weeks is considered APLS positive.

Inherited thrombophilia should include hyperhomocysteinemia, protein C and S deficiency, factor V Leiden mutation, antithrombin 3, and acquired to include protein C and hyperhomocysteinemia. For SLE, Antinuclear antibodies (ANA) test is recommended.

Endometrial biopsy is recommended in suspected cases of chronic endometritis. Testing for vaginal/cervical infection, if needed, can be done.

Genetic evaluation of miscarriage POC is recommended for all patients with a second loss or recurrent pregnancy loss, as it can identify a definite cause in 90% of miscarriages [2]. If sporadic aneuploidy is found to be the etiology of miscarriage, expensive RPL workup can be avoided. Karyotyping by 24-chromosome microarray analysis is recommended over FISH (Fluorescence in situ Hybridization) or metaphase G banding, as it does not require cell culture and has the ability to use archived tissue with a fast turnaround time. It also allows detection of microduplication and microdeletion. Maternal cell contamination can be minimized by careful tissue sampling. Home collection of miscarriage tissue can be offered to those who do not desire surgical management.

There is no consensus on diagnostic evaluation for immunologic mechanisms and dysregulation. [4]

Prepregnancy counseling for a healthy lifestyle, avoidance of toxic factors, and folic acid supplementation with basic investigations is recommended.