Recurrent pregnancy loss

Overview

While one miscarriage may warrant a visit to the doctor, two or more miscarriages should necessitate a thorough examination for reproductive disorders. Recurrent pregnancy loss (RPL) occurs when a woman has two or more clinical pregnancy losses (miscarriages) before the pregnancy reaches 20 weeks. Losses are categorised according to when they occur.

Only approximately 2% of pregnant women experience two successive miscarriages. Up to 50% of individuals with RPL do not have an identifiable cause. RPL is a complex and difficult circumstance in reproductive medicine that is stressful for patients, their families, and treating clinicians. When the cause of RPL is unknown, individuals may experience worry and uncertainty.

Definition of recurrent pregnancy loss

In the United States, recurrent pregnancy loss (RPL) is defined as two or more consecutive failed clinical pregnancies verified by ultrasound or histopathology, but the criteria in the United Kingdom is three or more consecutive early pregnancy losses. Up to 50% of instances of recurrent pregnancy loss do not have a definite explanation.

There are two forms of recurrent pregnancy loss: primary and secondary. Women who have never given birth to a live baby have primary, recurring pregnancy loss. Secondary recurrent pregnancy loss happens after a woman has given birth to a live baby.

Causes of recurrent pregnancy loss

The etiology of recurrent pregnancy loss (RPL) is broadly classified into the following:

• Genetic
• Anatomic
• Endocrine
• Antiphospholipid antibody syndrome
• Immunological
• Environmental factors

Genetic: 

One of the most prevalent causes of RPL is aneuploidy. Translocations that are balanced, reciprocal, or Robertsonian in the fetus might predispose to spontaneous miscarriage.

Anatomic:

RPL can be caused by congenital Mullerian tract abnormalities. Septate, unicornuate, bicornuate, didelphic, and arcuate uteri are some of the uterine anomalies that might contribute to RPL. The septate uterus is the most frequent congenital uterine abnormality.

Congenital uterine abnormalities were found in around 12.6 percent of individuals who experienced recurrent pregnancy loss. A woman's risk for RPL can also be increased by acquired uterine irregularities including as fibroids, polyps, and Asherman syndrome.

Endocrine: 

Hyperprolactinemia is linked to infertility and miscarriage by disrupting the hypothalamic–pituitary–ovarian axis, resulting in poor folliculogenesis and anovulation. Normal fertility is restored when the underlying problem is treated.

Thyroid problems, particularly hypothyroidism, have long been linked to infertility, poor pregnancy outcomes, and RPL. Overt hypothyroidism is simple to detect and treat. However, there is mixed evidence about the link between subclinical hypothyroidism and pregnancy loss.

The most often used serum thyroid-stimulating hormone (TSH) criterion for subclinical hypothyroidism is >2.5 mIU/L. In two recent cohort studies, women with RPL had a significant rate of subclinical hypothyroidism (classified as TSH >2.5 mIU/L) (19 percent and 21 percent ). LBRs in these individuals, however, were equivalent to those in euthyroid women.

In these individuals, a TSH level of 2.5 mIU/L is advised. Some studies have also discovered a link between thyroid antibodies and RPL in euthyroid individuals, with indications of a tendency toward lower miscarriage rates after therapy. To present, however, there is insufficient data to advocate regular thyroid antibody screening in euthyroid women with RPL.

Miscarriage is more likely in women who have polycystic ovarian syndrome (PCOS). Many processes, including insulin resistance and hyperinsulinemia, hyperandrogenemia, and enhanced plasminogen activator inhibitor-1 activity, are considered to be implicated. Changes in lifestyle, such as weight loss and exercise, improve insulin resistance and may reduce the incidence of miscarriage.

Metformin, an insulin-sensitizing medication, is often used in women with PCOS and has been found to improve weight management and glucose tolerance, decrease androgen production, and increase fertility. Studies on its effectiveness in lowering the risk of miscarriage in women with PCOS have shown contradictory findings, and there is inadequate evidence to suggest it for RPL. Metformin, on the other hand, is commonly administered in women with PCOS, is safe during pregnancy, and, together with weight loss, may be beneficial to PCOS patients with RPL.

Diabetes has been demonstrated to increase the chance of miscarriage, although appropriate preconceptional treatment dramatically reduces the risk back to normal.

Luteal phase deficit (LPD), or insufficiency, was initially recognized in 1949 as a cause of early miscarriage and RPL, although its definition and genuine influence on conception rates remain fiercely debated. The distinguishing feature is a lack of endogenous progesterone or its impact on the endometrium during the luteal phase, which interferes with proper implantation.

Many theories have been advanced, including insufficient follicular development, dysovulation, poor corpus luteum function, and aberrant endometrial responsiveness and receptivity. Thyroid illness and hyperprolactinemia are also hypothesized to induce LPD by affecting the hypothalamic–pituitary–ovarian axis and gonadotropin production.

Over the years, several diagnostic criteria have been utilized, including histologic dating of endometrial samples, luteal phase progesterone concentration, luteal phase duration (11 days), and basal body temperature. This has resulted in disparate occurrences of RPL in women ranging from 12% to 28%. Diagnostic tests for LPD, on the other hand, are not repeatable nor trustworthy, and have not been validated in large trials, hence they are not recommended in clinical practice.

There is also no agreement on how LPD should be managed. Several therapy regimens, in addition to addressing the underlying reason, have been used: ovulation induction, supplementary progesterone, supplemented progesterone plus estrogen, and human chorionic gonadotropin. Because of its availability, convenience of administration, and tolerability, progesterone supplementation is the most often utilized therapy. Details on progesterone therapy for RPL will be explored further down.

Antiphospholipid antibody syndrome (APLS):

The presence of antiphospholipid antibodies (aPL) characterizes antiphospholipid syndrome (APS), which has long been linked to RPL. Indeed, pregnant morbidity is one of two clinical criteria necessary to validate an APS diagnosis, the other being vascular thrombosis.

The prevalence of APS in women with RPL varies according to research, ranging from as low as 6% to as high as 42%, although it is widely believed to be 5%–20%. This is most likely explained by the use of nonstandardized laboratory-specific assays, as well as the many kinds of antibodies examined throughout time.

However, lupus anticoagulant, anticardiolipin antibody, and anti-2 glycoprotein I are the only ones now utilized to diagnose APS. When there is no underlying disease, APS is referred to as primary, and when it is coupled with other disorders, it is referred to as secondary. Other obstetric problems, including as preeclampsia, intrauterine growth restriction, and preterm, have been linked to aPL, and numerous pathways have been hypothesized.

aPL attacks the trophoblast, impairing trophoblastic invasion and causing incorrect release of human chorionic gonadotropin and growth factor, as well as triggering syncytiotrophoblast death and an inflammatory response via complement activation at the maternal–fetal interface.

They also attack the vascular endothelium, causing aberrant spiral artery development. Although all three types of antibodies are linked to RPL and obstetric difficulties, certain studies show that the risk and severity vary according on the type and relationship of antibodies. In patients with RPL, screening for aPL is part of the initial workup.

Environmental factors:

Cigarette smoking has been associated to an increased incidence of RPL and has been shown to impact trophoblastic function. In women who conceive spontaneously, obesity is related with an increased chance of recurrent pregnancy loss. Other lifestyle behaviors linked to an increased risk of spontaneous miscarriage include alcohol intake (3 to 5 drinks per week), cocaine usage, and high caffeine consumption (greater than 3 cups of coffee per day).

Immunological: 

Routine testing for hereditary thrombophilias in women with RPL is not yet suggested. When a patient has a personal history of venous thromboembolism in the context of a nonrecurrent risk factor (such as surgery) or a family with a known or suspected high-risk thrombophilia, screening for hereditary thrombophilias may be necessary. Prospective cohort studies have found no link between inherited thrombophilia and fetal loss.

Chronic endometritis

Persistent endometritis (CE) is described as chronic inflammation of the uterine lining, and some studies have found a higher frequency in women with RPL (10%–27%). Endometrial receptivity is hypothesized to be compromised by stromal infiltration of plasma cells, as well as altered expression of implantation-related genes, resulting in RPL but also infertility and recurrent implantation failure after IVF (IVF).

Several approaches have been used to establish the diagnosis of CE, but the gold standard is the detection of plasma cells in the endometrial stroma through immunohistochemical staining for syndecan-1 (CD138), a plasma cell marker ($5 on 10 nonoverlapping high-power fields). The cause is most likely infectious, and numerous antibiotic treatment regimens have been proposed, with doxycycline (200 mg per day for 14 days) being the most extensively utilized, with some studies indicating excellent results following therapy.

However, no randomized studies have been published to yet, and questions about the effect of CE on reproductive result, the patient group to screen, the treatment protocol, and the necessity for a biopsy to confirm remission persist. Because of the absence of clear data, numerous international organisations do not endorse CE screening.

Several additional infections have been explored as possible causes of preterm labor. Some research suggests that bacterial vaginosis (Mycoplasma hominis, Ureaplasma urealyticum), brucellosis, syphilis, cytomegalovirus, dengue fever, human immunodeficiency virus, rubella, and malaria are more common in women who miscarry spontaneously. 23 However, no causative relationship has been demonstrated, and it is not advised that asymptomatic women with RPL be tested or empirically treated.

History and Physical

A complete and detailed history should be collected, including all information of past pregnancy losses. The gestational age of the previous pregnancy loss is crucial to know since RPL usually develops at a comparable gestational age in subsequent pregnancies. It is also vital to understand the type of therapy for prior pregnancy loss, since dilatation and curettage might raise the risk of Asherman syndrome and cervical incompetence, both of which can predispose to RPL.

It is also critical to capture the patient's complete medical (thyroid issues, diabetes), surgical, and menstrual history. It is necessary to document a family and personal history of venous and arterial thrombosis, as well as a history of smoking, alcohol, narcotics, and exposure to environmental contaminants. A thorough general and pelvic exam should be performed as part of the physical examination.

Recurrent pregnancy loss workup

Evaluation of couples with RPL should be thorough and should include the following:

Assessment of Medical Problems

Diabetes, thyroid issues, and hyperprolactinemia should all be ruled out.

Genetic Evaluation

Karyotype evaluation of the couples is required to identify underlying balanced, reciprocal, or Robertsonian translocations or mosaicism that may be transferred to the fetus and cause RPL. Despite the limited yield and high cost of these tests, examining the karyotypes of couples with RPL should be considered.

Assessment of the Uterine Anomalies

There are numerous techniques that may be used to detect congenital and acquired uterine malformations, some of which are as follows:

• Pelvic ultrasound
• Saline infusion sonohysterography
• Hysterosalpingogram
• Hysteroscopy
• MRI is very valuable in identifying congenital uterine anomalies. 

Immunologic Work Up

Antiphospholipid antibody syndrome research must be carried out. Patients with RPL should have anticardiolipin antibody, lupus anticoagulant, and anti-beta 2 glycoprotein levels measured. Anticardiolipin antibody and lupus anticoagulant have been linked to pregnancy loss in studies, and testing for APAS is advised for individuals with RPL.

Progesterone Level

Serum progesterone levels should not be measured on a regular basis since they are not indicative of future pregnancy outcomes.

Endometrial Biopsy

A huge number of studies reveal that this test does not accurately predict a woman's reproductive status.

Testing for Infections

Routine vaginal and cervical cultures for chlamydia, gonorrhea, bacterial vaginosis, and TORCH serology tests are not relevant in the assessment of RPL in a healthy woman without symptoms.

Evaluation of products of Conception (POC)

The use of a 24-chromosome microarray study augments the ASRM (American Society of Reproductive Medicine) approved RPL evaluation considerably. All couples who have had two or more consecutive pregnancy losses should be provided genetic testing of miscarriage tissue acquired at the time of the second and subsequent pregnancy losses. A genetic analysis of miscarriage tissue combined with an evidence-based assessment for RPL will uncover a plausible or conclusive etiology in more than 90% of losses.

Recurrent pregnancy loss treatment

The therapy of RPL should focus on the underlying curable reason. Patients and their families should be made aware of the dangers, alternatives, and success rates associated with each possible treatment choice. By offering emotional support to these nervous couples, treatment outcomes can be boosted. Whenever feasible, reproductive endocrinologists and obstetricians should work together and communicate clearly.

• Medical Conditions

Women with thyroid disorders, diabetes, obesity, and other medical issues should be addressed as needed. Consultation with an endocrinologist is also an option for managing uncontrolled thyroid problems and diabetes. Patients who have increased thyroid peroxidase antibodies are at a significant risk of RPL and should be handled accordingly. 

• Chromosomal Anomalies                                                        

The first step in treating couples with chromosomal disorders is to send them to genetic counseling. Couples should be taught about the possibility of fetal chromosomal disorders in future pregnancies. They may decide to go through with

Prenatal genetic testing, such as preimplantation genetic diagnosis, chorionic villus sampling, or amniocentesis, is used to discover genetic defects in the fetus and determine next steps in therapy. Although embryos with uneven chromosomal configurations can potentially be screened out, PGT (preimplantation genetic testing) is not commonly recommended since the chances of a pregnancy with an imbalanced karyotype surviving into the second trimester are low.

• Uterine Anomalies

RPL caused by congenital or acquired uterine anomalies can be treated surgically. Some of the surgical techniques include hysteroscopic septum resection, adhesion lysis, myomectomy, and bicornuate uterus repair. When feasible, these surgical treatments should be referred to a reproductive endocrinologist. 

• Immunological                                                                                                                 

Aspirin and heparin are commonly used to treat patients with antiphospholipid antibody syndrome and RPL, and it appears to enhance pregnancy outcomes. This therapy, however, may enhance maternal outcomes but does not prevent RPL in women with thrombophilias. Aspirin and low molecular weight heparin (LMWH) are common drugs used to treat RPL.

New therapy approaches, such as TNF (tumor necrosis factor-alpha) inhibitors and granulocyte colony-stimulating factor (G-CSF), are showing promise in some cases of RPL. More thorough clinical trials, however, are required to further confirm or deny the advantages of these medications in the treatment of RPL patients.

Differential Diagnosis

Common

• Fetal chromosomal abnormality
• Idiopathic recurrent miscarriage

Uncommon

• Antiphospholipid syndrome
• Cervical incompetence
• Parental chromosomal abnormality
• Uncontrolled diabetes

Prognosis

Recurrent pregnancy loss (RPL) has a significant emotional and psychological burden on couples. It has been linked to sadness, anxiety, and low self-esteem. The most important independent risk factors for suffering subsequent pregnancy losses appear to be increasing mother age and the number of prior miscarriages.

Complications

Women who have recurrent pregnancy loss may endure emotional and mental distress, as this diagnosis has a negative impact on the women and their family. The couple may suffer as a result of the psychological impact of several pregnancy losses and the fear that the problem will never stop. RPL is fraught with frustration, and couples are always hoping for a good pregnancy while yet fearful of miscarrying again.

RPL has a detrimental influence not just on women and their families, but also on clinicians who treat them. Couples may experience unpleasant feelings such as anger, despair, frustration, and perplexity as a result. It may also have an impact on relationships, resulting in a lack of closeness.

Conclusion 

Recurrent pregnancy loss is a significant reproductive health concern that affects 2%–5% of couples. Uterine malformations, antiphospholipid syndrome, hormonal and metabolic problems, and chromosomal abnormalities are all common recognized causes. Other etiologies, such as chronic endometritis, hereditary thrombophilias, luteal phase insufficiency, and high sperm DNA fragmentation levels, have been postulated but are still regarded dubious.

Evidence-based therapies, such as surgical repair of uterine abnormalities or aspirin and heparin for antiphospholipid syndrome, have improved results for couples experiencing recurrent pregnancy loss throughout the years. However, about half of the cases remain unexplained and are treated empirically with progesterone supplements, anticoagulation, and/or immunomodulatory drugs.

Regardless of the cause, couples who experience recurrent pregnancy loss have an excellent long-term prognosis, and the majority eventually have a healthy live delivery. Multiple pregnancy losses, on the other hand, can have a severe psychological impact on afflicted couples, and numerous attempts are being made to enhance therapies and reduce the time required to obtain a successful pregnancy.