Definition –
The occurrence of repeated (three or more consecutive) pregnancies that end in miscarriage of the fetus, usually before 20 weeks of gestation.
• Prevalence –
One percent of women of reproductive age who conceive. Diagnostic evaluation of couples
• History –
The pattern, trimester, and characteristics of prior pregnancy losses should be reviewed. Exposure to environmental toxins and drugs, prior gynecologic or obstetric infections, and excluding the possibility of consanguinity are important.
• Physical examination –
may reveal evidence of maternal systemic disease or uterine anomalies.
• Laboratory tests –
Laboratory tests and imaging studies should be individually utilized. Etiology
Most couples will have no clear explanation for their recurrent pregnancy loss (RPL). Several alleged causes are controversial and anxious patients/physicians often explore empiric or alternative treatments with dubious benefit.
Idiopathic (>50%)
• Many couples never have a cause identified, even after extensive investigations. Informative and supportive counseling serves an important role because 60–70% of women with at least one previous live birth will have a successful next pregnancy.
Anatomic factors (10–15%)
• Uterine anomalies are most often associated with second-trimester loss. Congenital malformations result from müllerian tube fusion abnormalities and acquired lesions have a more controversial impact. Surgical revision may be helpful in some circumstances.
• Incompetent cervix also accounts for mainly second-trimester losses. Cerclage placement may be beneficial in selected patients.
Endocrine factors (10–15%)
• Luteal phase deficiency –
Luteal phase deficiency is purported to result from insufficient progesterone secretion by the corpus luteum, resulting in inadequate preparation of the endometrium for implantation and/or an inability to maintain early pregnancy. Two “out-of-phase” endometrial biopsies (in which histologic dating lags behind menstrual dating by ≤2 days) in consecutive cycles are required for the diagnosis. Progesterone supplementation is commonly prescribed, but therapeutic benefit is speculative.
• Metabolic disorders –
Metabolic disorders (hypothyroidism, poorly controlled diabetes, polycystic ovarian syndrome require diagnosis and treatment of the underlying disease. Mild or subclinical endocrine diseases are not causative.
Genetic factors (5–10%)
In certain chromosomal situations, although treatment may not be available, in vitro fertilization (IVF ) with preimplantation genetic diagnosis may be able to identify embryos with a reduced risk of another pregnancy loss which would then be transferred.
• Parental chromosomal abnormalities –
Parental chromosomal abnormalities are the only proven cause of RPL. The most frequent karyotypic abnormality is a balanced translocation– found most often in the female partner. Two-thirds are reciprocal (exchange of chromatin between any two non-homologous chromosomes without loss of genetic material). A third are Robertsonian (fusion of chromosomes that have the centromere very near one end of a chromosome [typically 13, 14, 15, 21, or 22] with loss of one centromere and two short arms). The overall risk of spontaneous miscarriage in couples with a balanced translocation is >25%. The only treatment option may be IVF with donor sperm or ova.
• Recurrent embryonic aneuploidy –
Recurrent embryonic aneuploidy may represent non-random events in some predisposed couples. Most aneuploid losses are the result of advanced maternal age. Prenatal diagnosis via amniocentesis or chorionic villous sampling may be useful in some situations – but no treatment is available.
Immunologic factors (5–10%)
• Antiphospholipid antibody syndrome –
It is an autoimmune disorder characterized by circulating antibodies against membrane phospholipids and at least one specific clinical syndrome (RPL, unexplained thrombosis, fetal death). The diagnosis requires at least one confirmatory serologic test (lupus anticoagulant, anti-cardiolipin antibody). The treatment of choice is aspirin plus heparin (or prednisone in some circumstances).
• Alloimmunity –
Alloimmunity (immunologic differences between individuals) has been proposed as a factor between reproductive partners that causes otherwise unexplained RPL. During normal pregnancy, the mother’s immune system is thought to recognize semiallogeneic (50% “nonself”) fetal antigens and to produce “blocking” factors to protect the fetus. Failure to produce these blocking factors may play a role, but there is no direct scientific evidence to support this theory and there is no specific diagnostic test. Immunotherapy has been used in an attempt to promote immune tolerance to paternal antigen.
Infection (5%)
Listeria monocytogenes, Mycoplasma hominis, Ureaplasma urealyticum, Toxoplasma gondii, and viruses (herpes simplex, cytomegalovirus, rubella) have been variously associated with spontaneous abortion, but none has been proven to cause RPL. Diagnosis can be made using cervical cultures, viral titers, or serum antibodies. Directed antibiotic therapy may be useful if a causative agent is identified. However, empiric treatment with doxycycline or erythromycin may be more cost-effective and efficient.
Other possible factors
• Thrombophilia –
Thrombophilia (propensity for blood clots) increases the risk of RPL. The most common types are factor V Leiden and prothrombin G2010A mutation. Anticoagulant therapy may improve the chances of carrying the pregnancy to term.
• Environmental toxins –
Environmental toxins such as smoking, alcohol, and heavy coffee consumption have been associated with an increased risk of spontaneous miscarriage, but not RPL. Regardless, use should be curtailed if possible.
• Drugs –
Drugs such as folic acid antagonists, valproic acid, warfarin, anesthetic gases, tetrachloroethylene, and isotretinoin (Accutane) are also speculative causes.
Prognosis
• If the likely cause can be determined, treatment is to be directed accordingly.
• Close surveillance during pregnancy is generally recommended for RPL patients who become pregnant. Couples are often anxious, frustrated, and on the verge of despair. Fortunately, the possibility of achieving a live birth is high.