Recurrent Pregnancy Loss

Etiology

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

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

Genetic: Aneuploidy is one of the most common causes of RPL. Balanced, reciprocal, and Robertsonian translocations in the fetus can predispose to spontaneous miscarriages.

Anatomic: Congenital Mullerian tract anomalies can cause RPL. Some of the uterine abnormalities which can predispose to RPL are septate, unicornuate, bicornuate, didelphic, and arcuate uteri. Septate uterus is considered to be the most common congenital uterine anomaly. A meta-analysis of several studies concluded that congenital uterine defects were present in about 12.6 percent of the patients with recurrent pregnancy loss.[5] Acquired uterine anomalies like fibroids, polyps, and Asherman syndrome can also increase the women's risk for RPL.

Endocrine: Maternal endocrine disorders like diabetes and thyroid dysfunction can cause RPL and must be evaluated and appropriately treated in patients with RPL. Hyperprolactinemia may be associated with RPL but is not proven.

Antiphospholipid antibody syndrome (APLS): accounts for about 8 to 42 percent of patients with RPL. APLS causes an increased risk of thrombosis and placental insufficiency, causing RPL.[6]

Environmental factors: Cigarette smoking is suggested to affect trophoblastic function and is linked to an increased risk of RPL. Obesity is independently associated with an increased risk of recurrent pregnancy loss in women who conceive naturally. Other lifestyle habits such as alcohol consumption (3 to 5 drinks per week), cocaine use, and increased caffeine consumption (more than 3 cups of coffee per day) are also associated with an increased risk of spontaneous miscarriages.

Immunological: Routine testing of women with RPL for inherited thrombophilias is not currently recommended.[7] Screening for inherited thrombophilias may be indicated when a patient has a personal history of venous thromboembolism in the setting of a nonrecurrent risk factor (such as surgery) or a  relative with a known or suspected high-risk thrombophilia. Prospective cohort studies have failed to confirm the association between hereditary thrombophilia and fetal loss.

Epidemiology

Only about 2 percent of pregnant women have two or more consecutive pregnancy losses.[2] Up to 50 percent of patients with RPL have no clearly defined etiology.[3]

Pathophysiology

RPL is a multifactorial condition that may be due to genetic, anatomic, endocrine, antiphospholipid antibody syndrome, immunologic, and environmental factors.

FOXD1 mutations play a central role in RPL. FOXD1 was defined as a major molecule involved in embryo implantation in mice and humans by regulating endometrial and placental genes. FOXD1 mutations in human species have been functionally linked to RPL's origin.[8]

History and Physical

A thorough and detailed history should be taken and must include all the details of previous pregnancy losses. The gestational age of prior pregnancy loss is critical to know, as RPL typically occurs at a similar gestational age in successive pregnancies. The method of treatment of previous pregnancy loss is also important to know, as dilation and curettage can increase the risk of Asherman syndrome, cervical incompetence, which can predispose to RPL.

It is also essential to document full medical (thyroid problems, diabetes), surgical, and menstrual history. Family and personal history of venous and arterial thrombosis, history of smoking, alcohol, drugs, and exposure to environmental toxins must be documented. Physical examination should include a detailed general exam and pelvic exam.

Evaluation

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

Assessment of Medical Problems

Studies should be performed to rule out diabetes, thyroid problems [9], and hyperprolactinemia. 

Genetic Evaluation

Karyotype assessment of the couples has to be offered to recognize underlying balanced, reciprocal, or Robertsonian translocations or mosaicism that might be transmitted to the fetus, causing RPL. Though these tests are of low yield and expensive, one should consider evaluating the karyotypes of the couples with RPL.[10][11]

Assessment of the Uterine Anomalies

There are several modalities that can be used to identify congenitally and acquired uterine anomalies, some of the valuable tools are the following:

• Pelvic ultrasound
• Saline infusion sonohysterography
• Hysterosalpingogram
• Hysteroscopy
• MRI is very valuable in identifying congenital uterine anomalies.[12]

Immunologic Work Up

Investigations for antiphospholipid antibody syndrome must be undertaken. Measurement of anticardiolipin antibody, lupus anticoagulant, and anti-beta 2 glycoprotein should be done for patients with RPL. Studies have reported that anticardiolipin antibody and lupus anticoagulant has been associated with pregnancy loss, and testing for APAS  for patients with RPL is recommended.[13]

Progesterone Level

Routine assessment of serum progesterone levels is not recommended, as it is not predictive of future pregnancy outcomes.

Endometrial Biopsy

A large number of studies show that this test is not reflective of fertility status in a woman.

Testing for Infections

In a healthy woman without symptoms, routine vaginal and cervical cultures for chlamydia, gonorrhea, bacterial vaginosis, and testing for TORCH serology are not useful in the evaluation of RPL. 

Evaluation of products of Conception (POC)

Using a 24-chromosome microarray analysis adds significantly to the ASRM (American Society of Reproductive Medicine) recommended RPL assessment. Genetic evaluation of miscarriage tissue obtained at the time of the second and subsequent pregnancy losses should be offered to all couples with two or more consecutive pregnancy losses. The combination of a genetic evaluation on miscarriage tissue with an evidence-based assessment for RPL will identify a probable or definitive cause in over 90 percent of miscarriages.[14]

Treatment / Management

The treatment of RPL should be directed towards the underlying treatable cause. Patients and their families should be informed about the risks, alternatives, and success rates of each available treatment option. Treatment success can be increased by providing emotional support for these anxious couples. There should be collaborative teamwork and clear communication between reproductive endocrinologists and obstetricians whenever possible.

Medical Conditions

Women with thyroid conditions, diabetes, obesity, and other medical problems should be treated as medically appropriate. Consultation with an endocrinologist is also a suitable option for the management of uncontrolled thyroid conditions and diabetes. Patients with elevated thyroid peroxidase antibodies are at high risk for RPL and should be managed appropriately.[15]

Chromosomal Anomalies                                                        

In couples with chromosomal abnormalities, the first step is a referral to genetic counseling. Couples should be educated on the potential likelihood of having fetal chromosomal abnormalities in future pregnancies. They may choose to proceed with

prenatal genetic testing, such as preimplantation genetic diagnosis, chorionic villus sampling, or amniocentesis to identify genetic anomalies in the fetus and decide about further treatment options.[16] Although embryos with unbalanced chromosomal arrangements can theoretically be screened out, PGT (preimplantation genetic testing) is not routinely advised since the likelihood of a pregnancy with an unbalanced karyotype surviving into the second trimester is low.[17](B2)

Uterine Anomalies

Congenital and acquired uterine abnormalities causing RPL could be managed surgically. Some of the surgical procedures are hysteroscopic septum resection, lysis of adhesions, myomectomy, and repair of a bicornuate uterus. Referral to a reproductive endocrinologist is appropriate for these surgical interventions whenever possible.[18](B3)

Immunological                                                                                                                         

Patients with antiphospholipid antibody syndrome and RPL are generally treated with aspirin and heparin, and it appears to improve pregnancy outcomes. However, in women with thrombophilias, this treatment may improve maternal outcomes but does not prevent RPL. Treatment strategies like aspirin and low molecular weight heparin (LMWH) are standard medications in RPL, although only a few placebo-controlled trials have proven their benefit with respect to live birth rate. There is emerging evidence that new treatment options, including drugs like TNF (tumor necrosis factor-alpha) inhibitors and granulocyte colony-stimulating factor (G-CSF), might be beneficial in some cases of RPL. However, more extensive clinical trials must be completed to further prove or disprove the benefits of these drugs in the treatment of patients with RPL.[19] Lipid emulsion infusions have been evaluated in only one RCT that tested whether a 250 mL infusion on the day of oocyte retrieval (with further infusions if there was a positive pregnancy test) could increase chemical pregnancy rates in patients with RPL with elevated peripheral blood NK cells (more than 12 percent) undergoing IVF.[20] The study concluded that Intralipid supplementation did not increase the frequency of chemical pregnancy. However, findings related to ongoing pregnancy and live birth should be investigated further.[20]

Unexplained RPL

A recent meta-analysis using strict criteria for defining unexplained RM found no RCTs involving prednisolone. Two recent meta-analyses of intravenous immunoglobulin (IVIG) use in patients with RPL found no evidence of improved live birth rates.[21](A1)

Differential Diagnosis

Common

• Fetal chromosomal abnormality
• Idiopathic recurrent miscarriage

Uncommon

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

Pertinent Studies and Ongoing Trials

The Progesterone in Recurrent Miscarriage (PROMISE) trial involved 836 women with idiopathic recurrent miscarriage randomized to receive either 400 mg of vaginal micronized progesterone twice daily or placebo from the time of positive pregnancy test to 12 weeks gestation.[22] There was no difference between the two groups in miscarriage or live birth rates. In contrast, another RCT involving 700 women also tested whether the same dose of vaginally administered natural progesterone would benefit unexplained RPL, but unlike the PROMISE trial, that trial commenced treatment in the luteal phase immediately after documentation of ovulation using either ultrasound or luteinizing hormone (LH) kits and continued until 28 weeks gestation. This Egyptian trial found significantly lower miscarriage rates (12.4 versus 23.3 percent) and higher live birth rates (92 versus 77 percent) in the treated group.[23]

Prognosis

Recurrent pregnancy loss (RPL) carries a tremendous negative emotional and psychological negative impact on couples. It is associated with depression, anxiety, and low self-esteem. Increasing maternal age, as well as the number of previous miscarriages, appear to be the most influential independent risk factors for having further pregnancy losses.

Complications

Women who experience recurrent pregnancy loss can struggle emotionally and mentally as this diagnosis carries an adverse impact on the women and their families. The couple can suffer due to the psychological impact of repeated pregnancy loss and the feeling that the problem might never end. RPL carries a great deal of frustration, and the couples are continuously aspiring to achieve a successful pregnancy and simultaneously afraid of miscarrying again. RPL carries a negative impact not only on women and their families but also on treating clinicians. It could leave couples with negative emotions like anger, sadness, frustration, and confusion. It could also affect relationships and results in a loss of intimacy.