What Causes Recurrent Pregnancy Losses?
A 32-year-old female, comes to our office for evaluation after three consecutive early pregnancy losses. Her first pregnancy was an anembryonic gestation diagnosed at 8 weeks, her second an early embryonic demise diagnosed at 8 weeks, and the most recent pregnancy ended in spontaneous abortion at 7 weeks. She has had no difficulty conceiving. She had early prenatal care for the first two pregnancies. Her initial prenatal visit for the third pregnancy was scheduled several days after the miscarriage.
She is in good health and takes no medications on a regular basis. She reports that her periods are every month and last 4-5 days with minimal dysmenorrhea. Her last menstrual period was 3 weeks ago. She has never had surgery other than for managing her early pregnancy losses and she is up-to-date on her health-care maintenance. She has no knowledge of any family history of inherited diseases, and her mother and sister have never had pregnancy loss or fertility issues. She denies smoking, alcohol use, or use of illicit substances. She works full time as a financial analyst. She has had one lifetime male partner, her husband, who is also in good health and is unaware of any family history of inherited diseases or pregnancy loss.
Recurrent Pregnancy Losses
The widely accepted definition of recurrent pregnancy losses is a history of three consecutive spontaneous pregnancy losses with or without a previous successful pregnancy. The ASRM has amended the definition to two losses for the initiation of clinical evaluation and possible treatment. Pregnancy loss is relatively common, occurring in up to 25% of recognized pregnancies. It is estimated that fewer than 5% of couples will have two consecutive pregnancy losses and 1% of couples will have three.
The differential diagnosis of recurrent pregnancy losses at early stages includes genetic abnormalities, antiphospholipid syndrome, inherited thrombophilias, hormonal and structural abnormalities, and smoking, caffeine, or alcohol use. The majority of non-recurrent early pregnancy losses are due to sporadic genetic abnormalities in the setting of normal parental karyotypes. These abnormalities are more common as maternal age increases due to reduction in oocyte number and quality. As the number of recurrent pregnancy losses at early stages increases, the probability of sporadic genetic causes decreases. A balanced translocation in either parent can lead to recurrent pregnancy losses and is estimated to account for 2-5% of recurrent pregnancy losses. The risk of spontaneous abortion is directly related to the amount and content of the genetic material in the translocation and can be identified by parental karyotyping. Despite the theoretical ability of Preimplantation Genetic Diagnosis (PGD) to detect chromosomal abnormalities in embryos, it has not been shown to increase live birth rates when compared to conservative management. Currently, there is no recommendation for screening with PGD.
Antiphospholipid antibody syndrome has been associated with early and recurrent pregnancy losses. It is present in approximately 15% of patients with recurrent pregnancy losses, and in only 2% of patients with normal obstetrical histories. The antibodies are thought to interfere with early placentation and development of vascular structures necessary for normal fetal growth. It is diagnosed by testing for the presence of anticardiolipin antibodies, lupus anticoagulant, and anti-β2-glycoprotein. Testing should be considered in patients who have a history of three or more first-trimester losses, one or more miscarriages of a morphologically normal fetus at ten weeks or later, or one or more second-trimester spontaneous pregnancy losses that cannot be attributed to another cause. The diagnosis of antiphospholipid antibody syndrome requires two positive tests at least 12 weeks apart.
Inherited thrombophilias, including Factor V Leiden, decreased Protein S or Protein C activity, antithrombin III deficiency, and prothrombin gene mutation have been theorized to be associated with pregnancy loss, specifically in the second trimester. There has been no conclusive evidence that inherited thrombophilias cause first-trimester or recurrent pregnancy losses, so testing is not recommended.
Diabetes and insulin resistance, thyroid dysfunction, and hyperprolactinemia have been implicated in recurrent pregnancy losses. Uncontrolled diabetes in early pregnancy results in fetal wastage and fetal malformations. There is some association of recurrent pregnancy losses with insulin resistance in the setting of mild blood glucose elevation. The metabolic syndrome and its persistent associated hyperinflammatory state have been suggested to be a contributor to early pregnancy loss, but this has not been proven. Hypothyroidism has been associated with early miscarriage with or without the presence of antithyroid antibodies. Elevated prolactin can interfere with successful implantation and maintenance of the corpus luteum in the first trimester. Live birth rates are increased with normalization of prolactin.
Structural uterine abnormalities can cause recurrent pregnancy losses, although reported incidences vary. Septate uteri have the highest association, but other anomalies such as arcuate uteri have also been implicated. Fibroids tend not to be a cause of miscarriage unless in a truly submucosal location. An initial evaluation of uterine anatomy with ultrasound is effective and relatively noninvasive. Additional imaging with sonohysterogram or hysterosalpingogram can be performed if a cavity defect is suspected. Septum resection by hysteroscopy has been shown in several studies to improve the live birth rate for those patients with previous losses.
Lifestyle choices, particularly tobacco, alcohol, and substance use, may contribute. Cigarette smoking and alcohol intake are associated with an increased risk of miscarriage. These modifiable risk factors also have implications for decreasing pregnancy risk and long-term health. Alcohol use of 3-5 drinks per week has been shown to increase the risk of fetal loss. Excessive caffeine intake, typically greater than three cups of coffee per day, is also associated with an increased risk of miscarriage. Even if not the primary cause, modification may help with the success of other interventions.
Production of adequate progesterone by the corpus luteum is necessary until approximately 12 weeks. Deficiencies of endogenous hormone production, termed luteal phase deficiency, have been hypothesized as a cause of recurrent pregnancy losses. Supplementation with exogenous progesterone has not been shown to improve outcomes in women with recurrent pregnancy losses, and testing for luteal phase deficiency is not recommended.
Evaluation begins with history, which needs to be obtained carefully, as recurrent pregnancy losses often provokes stress and anxiety in the patient and the partner. Information should be obtained on each pregnancy and its outcome. Records should be obtained whenever possible, as patient history alone may be inaccurate. Documentation of recurrent pregnancy losses by ultrasound or histology is preferred, and cytogenetic results should be reviewed. This will frequently require obtaining records from multiple institutions. Difficulty conceiving should be noted, as should whether the partner has had any pregnancies with another female, assessment for possible exposure to teratogens, and family history of autoimmune disease. Patients should be asked about smoking and alcohol and caffeine intake. Review of systems should obtain information about potential autoimmune disease, thyroid disease, or diabetes.
A complete physical exam should be performed and recommended preventative care should be up-to-date. Initial testing should include karyotype of both parents, pelvic sonogram, serum testing for TSH, prolactin, lupus anticoagulant, anticardiolipin antibody, and anti-β2-glycoprotein antibody. Other testing can be considered if results are inconclusive or if indicated by patient history. These tests may be done in a staged manner, with diagnoses suggested by history tested for first, or lower cost tests done first in patients with limited or no insurance coverage. No couple should be considered to have unexplained recurrent pregnancy losses until the evaluation is complete.
If testing reveals a specific cause, appropriate management should be initiated. Patients should be counseled to stop smoking and alcohol consumption and reduce or eliminate caffeine. Many patients, like this one, will have no clear cause identified. When the workup reveals no direct cause for recurrent pregnancy loss, discussion of the findings and reassurance for both parents are important. It is estimated that 50% of couples will have no identified cause for their recurrent pregnancy losses. Over 60% of these couples will have a live birth in the five years following the diagnosis. This percentage is higher in younger mothers and lower in women over 40. Success rates are higher in couples who have no difficulty conceiving, and for women who experience miscarriage at a later stage in the pregnancy. Presentation of the data showing that more than 50% of couples will have a successful pregnancy with conservative management and observation should be included in the counseling, as was done with this patient.
- Recurrent pregnancy losses affects approximately 1% of couples who desire conception,
- Causes of recurrent pregnancy losses include balanced translocations, antiphospholipid syndrome, diabetes, thyroid disease, elevated prolactin, uterine abnormalities, smoking and alcohol,
- Initial evaluation should include genetic analysis of the parents, screening for uterine structural abnormalities, hormonal evaluation (thyroid, prolactin, insulin resistance/diabetes), and immunologic causes (antiphospholipid antibody syndrome testing),
- There is no benefit to progesterone supplementation,
- The majority of couples with recurrent pregnancy losses will have no clear cause of pregnancy loss. The five-year live birth rate for couples with recurrent pregnancy losses with or without treatment is over 60%. Maternal age is the strongest predictor of future successful pregnancy.
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