Recurrent pregnancy loss (RPL) is also known as recurrent miscarriage or habitual abortion, and is a condition distinct from infertility. It is defined by two to three consecutive spontaneous abortions (miscarriages) before 20 weeks gestation. Approximately 1-5% pregnant women have a diagnosis ofRPL (40,000 – 200,000 U.S. couples/year). Although approximately 10-25% of all recognized pregnancies result in miscarriage, less than 5% of women will experience two consecutive miscarriages, and only 1% experience three or more. The basic normal miscarriage rate is 10% per pregnancy for ages 15-29 and as high as 55% for women >44 years old. In addition, for women with two consecutive losses and no live-born children 49% will have a loss in their next pregnancy, whereas for women with two losses and at least one live-born child 29% will have a loss in their next pregnancy.
It is well known that the incidence of a single miscarriage increases with female age in both normal and in RPL patients. This normal age dependent increasing miscarriage rate compounds the problem for women with RPL. When the cause of miscarriage is unknown, each pregnancy loss merits careful review to determine whether specific evaluation may be appropriate. Depending on the woman’s age, after two to three or more losses, a thorough evaluation is warranted. Couples who experience recurrent pregnancy loss may benefit from a medical evaluation and psychological support.
Potential Causes of RPL & Diagnostic Tests
The Physicians and the clinical and laboratory team at Advanced Fertility Care are highly adept at diagnosing, counseling, and treating simple and complex RPL conditions. There are several potentially known factors that may contribute to RPL, however in 50-75% of cases the cause remains elusive and unexplained. However, for those who fit the criteria, either a partial or complete evaluation should be performed and includes the following:
The incidence of chromosomal abnormality in couples experiencing RPL is 3-5%. Diagnosis is made by chromosome testing (karyotype) of both the male and female partner’s blood sample. Most RPL patients with a chromosome abnormality have no physical evidence of a problem other than their history of RPL itself and couples with a family history of genetic abnormality should be offered genetic counseling in addition to chromosome testing. Some abnormalities that may be discovered are:
- Translocation – A translocation occurs when genetic material is exchanged between chromosomes and is the most common inherited chromosome abnormality. The translocation is considered balanced if there is no net loss of genetic material and unbalanced if some material is lost during the translocation process. A significant percentage of genetically unbalanced (abnormal) sperm or eggs will form in translocation carriers. Thus, many adult translocation carriers will experience RPL and some will deliver babies with an unbalanced translocation causing mental retardation or other defects.
- Chromosome inversion – A less common chromosomal abnormality which involves reinsertion of a segment of a chromosome in the reverse order following chromosome breakage. This can lead to duplications or deficiencies of genetic material during sperm or egg formation. Similar to translocations, carriers of inversions may produce unbalanced embryos causing RPL and other defects.
- Single-gene mutations – Mutations in genes required for embryonic, placental, or cardiac development may result in RPL. There are no specific tests for these genes now, but completion of the human genome project has set the stage for this area of molecular diagnosis.
Some treatment options for couples found to have parental genetic abnormalities include:
- Pre-implantation genetic diagnosis (PGD) in combination with in vitro fertilization (IVF) which may allow some patients with genetic problems to conceive their own biological child. Please click here to read about IVF with PGD.
- Donor sperm or Donor Egg IVF may also be recommended treatments for some couples with a parental genetic cause for RPL.
In contrast to the rare finding of an inherited genetic cause, many early pregnancy losses are due to random chance chromosomal abnormalities in the developing embryo. Over 60% of miscarriages may be related to this random event which usually results in a missing or duplicated chromosome.
Reproductive age is defined as female age of 35 and above. The chances of pregnancy loss increases as a woman ages. Many women assume that reproductive success will naturally follow a healthy lifestyle. Unfortunately, living a healthy life and having “normal checkups” will never change the basic fact that a woman is born with all the eggs she will ever have and that aging eggs have been subjected to a lifetime of potential environmental reproductive toxins. A good number of women with unexplained infertility or RPL are experiencing accelerated reproductive aging and aging eggs are more likely to be genetically abnormal. Thus, advancing female age (and increasing male age in some cases) will cause an increased number of genetically abnormal embryos.
Scientists have shown by the time a woman turns 40, at least 50% of all her eggs are chromosomally abnormal. Subsequently, after age 40, more than 1/3rd of all pregnancies result in miscarriage with abnormal numbers of chromosomes.
Diagnosis is based either on age alone or on hormonal blood testing for ovarian function. This testing should include a “day 3 FSH level” or the “clomid challenge test”, also known as the “CCCT”. In addition AMH (anti Mullerian hormone) levels may also be assessed. Click here for more information on Ovarian Testing. These tests may uncover cases of abnormal ovarian function or “decreased ovarian reserve” occurring in women younger than expected which ultimately increases the risk of embryonic aneuploidy (abnormal chromosome numbers), adding to the risk of RPL and lowered pregnancy rates. Although some patients with abnormal hormonal testing results will conceive on their own, many others will require more aggressive infertility therapy.
Uterine Anatomic Abnormalities
It is estimated that distortion of the uterine cavity may be found in 10-20% of women with RPL. Diagnostic evaluation may include (hysterosalpingogram – HSG) or an ultrasound procedure (sonohysterogram), or hysteroscopy. Findings may include:
Congenital abnormalities: contribute to RPL through implantation failure or may cause late losses in some cases. Although some women can have normal outcomes with an abnormality in place, it is generally believed that loss rates can approach 70% without correction.
- Uterine Septum – The most common uterine abnormality causing reproductive loss is the uterine septum. The septate uterus is corrected by hysteroscopic septoplasty, an outpatient surgical procedure. Patients with a uterine septum have excellent outcomes after repair with delivery rates approaching those found in the normal obstetrical population.
- Bicornuate Uterus – Commonly referred to as a “heart-shaped” uterus, it is a type of uterine malformation where two “horns” form at the upper part of the uterus. A bicornuate uterus is formed during embryogenesis when the fusion of the upper part of the genital tract is altered. A bicornuate uterus is estimated to occur in 0.1-0.5% of women in the U.S. Some of the negative outcomes related to a bicornuate uterus are: recurrent pregnancy loss, preterm delivery, and malpresentation at delivery (breech birth or transverse presentation). Ultrasound alone cannot diagnose a bicornuate uterus and requires surgical evaluation or MRI.
Myomas (Fibroids) – Fibroids are benign growths that can cause many reproductive problems, including pregnancy loss. Myomas that distort the uterine cavity (termed submucosal) may cause implantation failure, resulting from decreased blood supply to the endometrium, and should be surgically removed in RPL patients.
Asherman’s syndrome – Scarring inside the uterus resulting from infection, retained products of conception, prior D&C, or previous uterine surgery. When possible, treatment consists of outpatient hysteroscopic surgical correction. Outcomes are dependent on the amount of original scar tissue present. In severe cases, a gestational carrier may be necessary.
Hormonal Abnormalities & Metabolic Problems
The incidence of hormonal abnormalities in women with RPL is approximately 10-15% and if patients with PCOS are included, significantly higher. Endocrine factors may include: low progesterone levels (luteal phase deficiency), thyroid disorders, pituitary disorders (hyperprolactinemia), and PCOS. In many of these cases, routine diagnostic blood work can identify a particular problem which may be easily treatable.
- Hyperprolactinemia – Oversecretion of pituitary prolactin can be caused by a small pituitary tumor. Diagnosis usually relies on hormone levels, exclusion of other causes of hyperprolactinemia (hypothyroidism, medication use), and ultimately MRI imaging of the pituitary which can identify a small benign tumor in the majority of patients. High prolactin levels can cause breast milk secretion, anovulation, and luteal phase defect.
- Thyroid disorders – Underactive thyroid (hypothyroidism) is a common disorder found among reproductive age women. Blood thyroid hormone levels (TSH and Free thyroxine) are used to diagnose this disorder. It is now believed that very minimal thyroid disease (sub-clinical hypothyroidism) may cause RPL and pregnancy complications nearly as much as more obvious thyroid disease. Treatment consists of normalizing thyroid function with thyroid hormone replacement therapy. Ovulatory problems and the possibility of luteal phase defect may be corrected by thyroid hormone replacement. Pregnancy loss rates are reduced to near normal levels when the disorder is corrected. Resolution may take several months after starting therapy. Calcium replacement with 500-1000mg supplementation while on thyroid replacement therapy is advised to lower the risk of osteoporosis during prolonged therapy.
- Polycystic Ovarian Syndrome (PCOS) – This disorder of excess male hormones, anovulation, and abnormal insulin metabolism, “insulin resistance” is associated with up to a 50% miscarriage rate in patients
- Luteal Phase Defect (LPD): LPD is a controversial cause of RPL. This can be a disorder of either low progesterone production by the ovary or low uterine response to progesterone. In many cases, this is a difficult disorder to diagnose. Given that the tests for diagnosing LPS are mostly unreliable and relatively costly (multiple progesterone measurements) and invasive (endometrial biopsy), Advanced Fertility Care Physicians opt to treat all their patients empirically with luteal vaginal progesterone support, since in general there is minimal risk to doing so and the potential benefits may be significant.
It is estimated that less than 5% of RPL is related to immune causes. Autoimmune disease (against self) refers to the abnormal immunologic response of the woman to her own tissues. This response may subsequently carry over to produce RPL.
Immune causes of this type include:
- Antiphospholipid syndrome (APS): Characterized by significant levels of anticardiolipin antibodies (ACA) and /or lupus anticoagulant (LAC) and one or more clinical features, including RPL, intrauterine fetal death or blood clotting. APS is both an autoimmune and thrombophilic disorder (see below). In general, antibody levels found in moderate to high levels can be associated with RPL. APS is the cause of RPL in five percent of women and is most commonly associated with second trimester pregnancy loss. It may also cause very early loss in the form of implantation failure. Five percent of the normal population of reproductive women may be positive for low levels of antibodies associated with APS. Treatment of + ACA and/or +LAC patients consist of low- dose aspirin, beginning after ovulation and continued throughout pregnancy, combined with injectible Heparin 5000 units twice a day, usually beginning with a positive pregnancy test. Alternatively, low molecular weight heparin (Lovenox 40mg injections once daily) can also be used and is easier to manage.
- Antinuclear antibody (ANA) / Rheumatoid Factor (RF): Two other markers of autoimmune disease which has also been associated with systemic lupus and rheumatoid arthritis and linked to RPL. Easily tested for with blood tests.
Thrombophilic Disorders (Excessive blood clotting)
Hypercoagulable conditions are inherited disorders that raise a woman’s risk of serious blood clots and may also increase risks of pregnancy loss mostly in the second half of pregnancy. These conditions may be either inherited or acquired and may cause RPL and pregnancy complications. Testing is generally performed if no other cause of RPL can be easily identified or if there is a significant family or personal history of clotting or stroke. Prior unexplained fetal death (loss of heartbeat after 8 weeks), severe fetal growth restriction with no other identifiable cause, and early toxemia (preeclamsia) during pregnancy would be another indication for testing. Diagnosis is based on blood testing for Factor V Leiden mutation, Prothrombin gene mutation, lupus anticoagulant, Antithrombin III deficiency, Protein C and S deficiency, and hyperhomocysteinemia (MTHFR mutation).
- As with autoimmune disorders, thrombophilic disorders can be treated with baby aspirin and/or heparin. See section on Autoimmune Disorders. Live-born rates can be as high as 70- 80% overall if properly treated.
- Hyperhomocysteinemia (MTHFR mutation) – Treated with increased folic acid (2-5 mg daily, vitamin B6, B12 – Folgard Rx) prior to and during gestation.
Male Reproductive Abnomalities
There is increasing evidence within the scientific literature that abnormal integrity of sperm DNA may affect embryo development and contribute to increased miscarriage risk (in some cases upto 50%). The sperm chromatin structure assay (SCSA) is a specific test that is sent to an outside laboratory that assess for increased percentage of DNA fragmentation and risk for miscarriage. It has also been shown that male age, particularly in men over fifty, may be associated with increased risk for RPL as a result of increased DNA fragmentation and decreased sperm integrity.
Outcomes With and Without Medical Therapy
- Approximately 50% of patients experiencing RPL will have a cause identified through routine medical testing with a slightly higher percentage of abnormalities being detected with the addition of IVF and preimplantation genetic screening (PGS).
- Approximately 70% of couples experiencing RPL will have a liveborn child without medical therapy. Most of these patients will be < 35 years old.
- Benefits of medical therapy may include:
- Provides assistance to the 30% of couples destined to have a low chance of a liveborn child without therapy.
- Helps to shorten the time interval to a successful outcome.
- Lower the risk of more losses before a successful outcome.