Recurrent pregnancy loss (RPL) is indeed a harrowing ordeal, not just for the patients but also for the healthcare providers tasked with their care. According to a comprehensive review published in 2023, a staggering 2.5 million cases of recurrent pregnancy loss occur worldwide annually, underscoring the immense burden it imposes.

The epidemiology of RPL highlights its impact, affecting nearly 1% of fertile couples and resulting in 1-2% of pregnancies miscarrying before 24 weeks. The incidence of miscarriage notably increases with age, reaching up to 9-12% for women up to 35 years old and up to 50% for women over 40. Definitions of RPL have evolved since 1977, with ongoing efforts to establish consensus and guidelines. Discrepancies exist among organizations, with some considering two consecutive losses as RPL, while others require three losses, and definitions may include consecutive and non-consecutive losses. The weight of the fetus, gestational age, and histopathological evidence are factors considered in defining RPL. It can be categorized as primary (no previous live birth) or secondary (previous live birth followed by pregnancy loss).

Anatomical factors contribute to approximately 10 to 15% of RPL cases. Autoimmune factors are implicated in around 20% of cases, while genetic factors account for 2% to 5%. Infections play a role in 0.5 to 5% of cases, and endocrine disorders contribute significantly, ranging from 10% to 20%. These endocrine disorders may include hyperprolactinemia, thyroid abnormalities (both hypo- and hyperthyroidism), diabetes, and PCOS, with luteal phase defects being particularly noteworthy, affecting 40 to 50% of patients. However, a significant portion, around 40 to 50% of cases, remain unexplained despite extensive investigation. These unexplained cases encompass non-APS (antiphospholipid syndrome) and other undetermined pathologies.

Immunologically, women with recurrent spontaneous miscarriages often exhibit a more significant bias towards a pro-inflammatory cytokine profile, specifically the TH1 type, compared to women with healthy pregnancies. A shift from Th1 to Th2 cytokine is typically observed in healthy pregnancies, indicating a favorable environment for maintaining pregnancy and supporting fetal development.

Endocrine factors, including thyroid abnormalities, PCOS, hyperprolactinemia, and luteal phase defects, can significantly impact pregnancy outcomes. Anatomical factors, whether congenital or acquired, contribute to RPL by reducing intrauterine volume and impairing vascular supply. Congenital uterine anomalies such as unicornuate, bicornuate, and septate uterus can predispose to recurrent pregnancy loss by altering the uterine environment and affecting implantation and fetal development. Acquired uterine abnormalities, such as uterine leiomyomas, polyps, incompetent cervix, etc., may result from scarring or other structural changes due to previous surgeries or infections, further complicating the pregnancy.

Inherited thrombophilia presents another significant concern, with certain factors predisposing individuals to venous thromboembolism. These factors include mutations in factor V Leiden, prothrombin gene, protein C and S deficiencies, antithrombin III deficiency, and MTHFR mutation. In thrombophilic conditions, abnormal clot formation occurs, leading to larger clots that persist and impede pregnancy progression.

 Antiphospholipid syndrome, an autoimmune disorder, is characterized by antibodies such as lupus anticoagulants, anticardiolipin antibodies (IgM/IgG), and anti-beta2 glycoprotein antibodies. These antibodies increase the risk of thrombosis and can adversely affect various organs, including those involved in pregnancy.

Genetic factors also play a significant role at both the embryo and parental levels. Chromosomal abnormalities, particularly in the early stages of pregnancy, often lead to miscarriages. Embryonic anomalies may include monosomy or trisomy, while parental-level anomalies may involve balanced structural chromosomal abnormalities, such as reciprocal or Robertsonian translocations, which can result in unbalanced translocations in the fetus. 

Another essential aspect to consider in modern times is lifestyle factors, which significantly influence pregnancy outcomes. Smoking, alcohol consumption, drug use, heavy caffeine intake, obesity, and stress all play crucial roles. Nicotine and alcohol, for instance, can adversely affect egg and sperm quality. Historically, discussions about male factors regarding smoking, alcohol, and drug use are now pertinent for females as well, considering their impact on fertility and pregnancy. Coffee consumption, often overlooked, can also have implications, especially when excessive. Obesity, recognized as a significant contributor to infertility and pregnancy complications, requires attention. Stress, whether from work, personal life, or family dynamics, is another critical factor implicated in miscarriages.

A thorough history encompassing medical and family backgrounds is fundamental. Additional screening encompasses immunological, endocrinological, anatomical, thrombophilia, antiphospholipid, and genetic factors. Immunological screening, including HLA testing, is selectively employed based on clinical necessity. Similarly, anti-thyroid antibody testing is recommended only when indicated, as not all patients require it. A comprehensive pregnancy history detailing previous losses and live births is invaluable. HLA testing may be warranted in cases of autoimmune disorders like reactive arthritis, where recurrent miscarriages are anticipated. Conversely, routine anti-thyroid antibody testing is not universally recommended for all patients with recurrent pregnancy loss.

Further considerations regarding cytokine testing include refraining from routine use and avoiding polymorphism testing in women with RPL. Antinuclear antibodies may be considered for explanatory purposes, while natural killer (NK) cell testing is not universally recommended for all patients.

Endocrinological screening refers to comprehensive testing, including thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), thyroid peroxidase (TPO) antibodies, prolactin, and blood sugar levels, is advisable for all patients. This recommendation stems from the high prevalence of subclinical hypothyroidism and thyroid autoimmunity in women with RPL, coupled with potential treatment options. Abnormal TSH levels should prompt further evaluation with T4 testing.

Reliance on history and physical examination is paramount for diagnosing PCOS, as no specific test definitively confirms the condition. Insulin metabolism testing is not universally recommended for all patients. Similarly, testing for luteal phase insufficiency, such as serum progesterone levels or endometrial biopsy, is not routinely advised. History, including menstrual cycle length, is considered more informative in assessing luteal phase adequacy.

Anatomical investigations are best conducted using ultrasound, with 3D ultrasound preferred due to its high sensitivity and specificity in evaluating uterine anatomy. This imaging modality can effectively differentiate between uterine anomalies, such as septate or bicornuate uterus. Magnetic resonance imaging (MRI) is not typically the first-line option, with 3D ultrasound preferred. However, if 3D ultrasound is unavailable, MRI may be considered.

Additionally, all women with recurrent pregnancy loss should undergo a 2D ultrasound to assess for adhesions. Screening for antiphospholipid syndrome involves testing for lupus anticoagulant and anticardiolipin antibodies (IgM) after two pregnancy losses, with consideration for beta-2 glycoprotein antibodies screening after the same number of losses. For antiphospholipid syndrome, a combination of aspirin and low molecular weight heparin has shown higher pregnancy rates compared to aspirin alone. This approach is recommended to increase the likelihood of a successful pregnancy.

Congenital malformations, such as uterine septum, may require treatment, while bicornuate uterus typically does not necessitate intervention unless associated with complications. Procedures like hysteroscopic septum resection can enhance uterine cavity morphology. Cervical cerclage is reserved for specific cases, such as a history of second-trimester pregnancy loss or cervical insufficiency.

Genetic counseling is essential for identifying hereditary factors contributing to RPL. Assisted reproductive techniques, including in vitro fertilization (IVF) with pre-implantation genetic diagnosis (PGD) or donor gametes, may be recommended based on genetic findings.

Lifestyle modifications play a significant role in management. Male partners should be advised to reduce smoking and manage obesity. Medications that may affect sperm quality, such as corticosteroids, should be reviewed and adjusted if necessary. Varicocele repair and sperm selection techniques like intracytoplasmic sperm injection (ICSI) can improve fertility outcomes. Antioxidant supplementation, such as vitamin E and coenzyme Q10, may mitigate oxidative stress.

Nonconventional treatments like Chinese herbal medicine, acupuncture, and antioxidant therapy have also been explored as adjunctive measures to reduce reactive oxygen species and enhance reproductive outcomes.

Natural micronized progesterone is crucial in managing RPL. Clinical evidence supports the use of vaginal micronized progesterone in RPL. The PRISM and PROMISE trials demonstrated a higher life birth rate with vaginal micronized progesterone, especially in women with a history of multiple miscarriages. 

A study by Ismail et al. showed that initiating progesterone treatment in the luteal phase before implantation and continuing until the 28th week of gestation led to lower miscarriage rates and higher life birth rates. This study also observed significant immunomodulatory effects of progesterone, reflected in decreased Th1 cytokines and increased Th2 cytokines throughout pregnancy.

Guidelines from various sources offer recommendations for managing RPL and threatened miscarriages. The French Clinical Practice Guidelines advocate for daily treatment with vaginal progesterone up to 34 weeks of gestation for women experiencing threatened late miscarriage and isolated undilated shortened cervix, provided there are no uterine contractions. According to the ESHRE Guidelines, vaginal progesterone may enhance the life birth rate in women who have experienced three or more pregnancy losses and vaginal blood loss in subsequent pregnancies.

Meanwhile, based on the findings of the Cochrane Review, supplementation with thyroxine (Thy) is recommended for women with unexplained recurrent miscarriages, potentially reducing the rate of miscarriage in subsequent pregnancies. NICE Recommendations advise offering progesterone to women who encounter bleeding in early pregnancy and have a history of miscarriage.

The FOGSI Position Statement supports the utilization of micronized progesterone, specifically 400 mg twice daily vaginally, up to 28 weeks of pregnancy for managing recurrent pregnancy loss and threatened miscarriage.