Causes of Repeat Pregnancy Loss

Here is a list of possible causes of repeat pregnancy loss (RPL).  Unfortunately, about 50% of couples are not able to find a cause of their repeat loss and receive a diagnosis of “unexplained recurrent miscarriages.” In this group the chance of a successful future outcome can be as high as 50-60% depending upon maternal age.

Please note this is for use as a guide only. All decisions about RPL testing should be discussed with your doctor. Click here to learn more about how to test for the issues below.

1. Fetal Genetic Abnormalities

Chromosomal abnormalities in the fetus account for about 60% of sporadic losses. Trisomies (an extra chromosome) is the most frequent and is related to maternal age. Often these chromosomal abnormalities are a random occurrence and attributed to “bad luck.” This may be true, especially at the two loss stage,  but parents should undergo chromosomal analysis after two losses to rule out any structural rearrangement of chromosomes they might be passing down (see #2).

Testing: Testing the products of conception is available, especially after a D&C. If you miscarry at home, try to save the passed tissue for testing.

2. Parental Genetic Abnormalities

The incidence of chromosomal abnormality in the parents experiencing RPL is 3-5%. Most RPL patients with a chromosome abnormality have no physical evidence of a problem other than their history of RPL. Couples with a family history of genetic abnormality should be offered genetic counseling. Known and suspected types of parental chromosomal abnormalities include:

• Translocation – A translocation occurs when genetic material is exchanged between chromosomes. 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 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 is a chromosome inversion. This 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.
• Single-gene mutations – Mutations in genes required for embryonic, placental, or cardiac development may result in RPL. Unfortunately, there are no specific tests for these genes now.

Testing: Both the mother and father should have chromosome testing, called a karyotype, using a blood sample.

Treatment Options: Pre-implantation genetic diagnosis (PGD) in combination with IVF may allow some patients with genetic problems to conceive their own biological child. Donor sperm or donor egg is also an option.

3. Uterine Anatomic Abnormalities

It is estimated that 10-20% of RPL results from anatomic abnormalities of the uterine cavity and and are a significant cause of both infertility and RPL. These abnormalities are typically congenital (present from birth) and are referred to as Mullerian anomalies, as the uterus develops from a specialized type of tissue called Mullerian tissue. During embryonic development, a female fetus actually starts out with two small uteri (plural o uterus). As the fetus develops, each uterus migrates toward the middle of the patient’s body where it fuses with the uterus from the other side. Under normal circumstances, the wall where the two uteri join reabsorbs completely, resulting in a triangular shaped uterine cavity. Any alteration of this development can lead to a Mullerian anomaly.

The most common congenital anomalies are the following:

• Septate Uterus – A septum occurs when the two uteri fuse but the wall between them only partially reabsorbs. The remaining (unreabsorbed) tissue at the top of the uterus behaves like scar tissue – it has decreased blood flow and may lack the receptors found in normal uterine linied that are necessary for implantation to occur and to nurture an embryo.
• Bicornuate Uterus – A bicornuate (Latin for “2 horns”) uterus occurs when the two uteri only fuse at the very bottom leaving a large reabsorbed vertical wall between the two cavities. In this condition, the patient has two small uterine cavities and a single cervix. Achievement of pregnancy is possible, but significantly reduced. In addition, premature labor is likely as the uterus cannot grow as large as it normally would in a term pregnancy.
• Unicornuate Uterus – When only one of the two uteri forms during embryologic development it is called a unicornuate uterus (Latin for “1 horn”). Both ovaries will still be present, but there is only one fallopian tube. The chance of pregnancy in these patiens is about 60% of that in a patient with a normal uterus.
• Uterine Didelphys – On very rare occasions, both uteri are present but they fail to fuse at all. This results in two separate uteri (each with its own fallopian tube and cervix), a condition called a uterine didelphys. This is easily recognizable by a general gynecologist.

Testing: Abnormalities are diagnoses with an X-ray procedure called hysterosalpingogram (HSG) or an ultrasound procedure called sonohysterogram (SHG).

Treatment options: With the exception of the uterine septum, these abnormalities are generally not repaired because the chance of improving pregnancy outcome is typically worse following surgical repair than it is without repair. However, surgical repair of a septate uterus dramatically improves pregnancy outcome. The septate uterus is corrected by a hysteroscopic septoplasy, an outpatient surgical procedure.

The most common acquired uterine abnormalities are:

• Myomas (Fibroids) – Fibroids are benign growths that can cause many reproductive problems, including pregnancy loss (although not all women with fibroids will experience reproductive problems). Fibroids that distort the uterine cavity may cause implantation failiure, resulting from decreased vascularization of the endometrium, and should be surgically removed in RPL patients.
• Asherman’s Syndrome – Scarring inside the uterus resulting from infection, retained products of conception, D&C, or previous uterine surgery. Treatment consists of hysteroscopic surgical correction. At times, a gestational carrier may be necessary.

A less common abnormality:

• Cervical Incompetence – Responsible for second trimester fetal loss, this diagnosis is based on clinical history of very early rupture of membranes without prior uterine contractions. Cervical cerclage is the treatment of choice. Occasionally, a surrogate is required.

3. Hormonal and Metabolic Factors 

• Hyperprolactinemia – This disorder of pituitary prolactin oversecretiom is usually caused by a small pituitary tumor. Diagnosis relies on hormonal measurements. MRI imaging of the pituitary will reveal a small benign tumor in the majority of patients. Elevated prolactin may cause breast milk secretion, anovulation, and possible luteal phase defect. Treatment requires therapy with one of sevaral dopamne agonust medications.
• Thyroid disfunction – Hypothyroidism is a common disorder found among reproductive age women. Diagnosis relies on demonstrating an elevated thyroid stimulating hormone (TSH) level. Thyroid levels can be monitored with the use of thyroid hormone replacement therapy. Pregnancy rates are reduced to near normal when the disorder is corrected. It is now believed that even very minimal thyroid disease (subclinical hypothyroidism) may cause RPL and pregnancy complications nearly as much as m ore obvious thyroid disease.
• Diabetes – Although an infrequent cause of RPL, if untreated and undiagnosed, diabetes can cause sever birth defects and RPL. Normalization of blood sugar control prior to conception is mandatory.

4. Advanced Reproductive Age

Advanced maternal age is defined as a female age 35 and over. Aging eggs have been subjected to a lifetime of unseen environmental toxins and are more likely to be genetically abnormal. A good number of women with unexplained infertility or RPL are experiencing accelerated reproductive aging.

Testing – Diagnosis is based on either age alone, or on blood testing for a “day 3 FSH level” or the “clomid challenge test” (CCCT).  These tests may uncover cases of abnormal ovarian function or “decreased ovarian reserve” occurring in women younger than expected.

Treatment – Patients with “elevated Day 3 FSH” can be treated with ovulation induction drugs, IVF with patients own eggs with the use of PGD, or using donor eggs with IVF.

5. Polycystic Ovarian Syndrome (PCOS) 

PCOS is a disorder of androgen excess, annovulation, and altered insulin metabolism, and is associated with up to a 50% miscarriage rate in patients <35 years old.

Testing – Typical diagnostic tests include testosterone and DHEAS levels, fasting insulin/glucose ratio, FSH and lH levels, and ovarian ultrasound evaluation.

Treatment – Consists primarily of inducing ovulation to generate a pregnancy combined with use of Glucophage (Metforim).

6. Hematologic or Immunologic Causes

When a pregnancy attaches to the uterine wall, it gets nourishment and oxygen from the mother by way of the placenta. This circulatory connection is critical to the survival and growth of the baby. Some miscarriages are caused by blood clots that form in the small vessels of the placenta, as these clots prevent the transfer of either nutrition or oxygen to the fetus. These clots may be caused by abnormalities in the normal blood clotting mechanism. There are three basic causes.

• Antiphospholipid antibody syndrome (APAS) – APAS has been reported to occur in 3%-15% of women with RPL and is most commonly associated with second trimester loss. The only test that been demonstrated to correlate with RPL is the anticardiolipin antibody test, a simple blood test.  Treatment consists of low-dose aspirin, beginning after ovulation and continued throughout pregnancy, combined with injectible Heparin 5000 units twice a day.
• Lupus Anticoagulant – Like APAS, this is a disorder in which blood clots occur within the small vessels of the placenta. As with APAS, a simple blood test can detect the presence of lupus anticoagulant.
• Thrombophilias – This is a group of disorders that includes such conditions as deficiencies of factor V Leiden, Prothrombin gene mutation, protein C, protein S, and hyperhomocysteinemia (MTHFR mutation). It remains controversial whether thrombophilias cause RPL. Treatment includes low-dose aspirin and Heparin.

7. Luteal Phase Defect (LPD)

LPD is a controversial cause of RPL. This condition, called “luteal phase inadequacy”, is thought to result from inadequate progesterone production, leading to a disorder in which the development of the uterine lining is not synchronized with the development of the embryo.  Therefore when the embryo tries to attach to the uterine wall, an unstable attachment may occur which may lead to miscarriage. Physicians oftentimes differ in their diagnostic evaluation of this disorder.

Treatment – Primarily consists of inducing ovulation to produce improved egg production (folliculogenesis) with either Clomid or Progesterone, which, in turn, will correct a luteal phase defect on the majority of patients. Patients may also be administered progesterone supplementation in addition to ovulation induction.

9. Lifestyle Factors/Toxin Exposure

Cigarette smoking, alcohol and cocaine use, and increased caffeine (more than 3 cups of coffee a day) have been reported to increase the risk of miscarriage. Cigarette smoking has also been linked to ovarian damage, diminished ovarian reserve and possible earlier than expected menopause. Exposure to ionizing radiation, mercury and lead are also contributors to pregnancy loss.

10. Male Reproductive Abnormalities

Males with significant, persistent abnormal sperm morphology (abnormal shape) may father a higher number of genetically abnormal embryos. It is also possible that some cases of RPL may be related to increasing male age – particularly in men over 50 years old.

Testing: Diagnosis requires several semen analyses. Also testing the sperm DNA fragmentation may also predict the presence of higher than average percent of genetically abnormal sperm.

Treatment: Varicocele (when found in the testicles) repair has been shown to improve sperm morphology. A sperm selection device, the PICSI dish, has been evaluated for use during IVF/ICSI to aid selection of the more genetically normal sperm. Use of antioxidants and vitamins may also improve sperm parameters.

Vitamins that are thought to aid male fertility include: Vitamin C (500 mg/day), Selenium (200 mcg/day), Co Q10 (200 mg/day), Vitamin E (200 IUs/day), Folic Acid (800 mcg/day), L-carnitine (1,000mg/day), and a multivitamin that contains no more than 20 mg of zinc and 200 IUs of Vitamin E. Some supplements on the market geared toward male fertility are Conception XR for Men, Coast Science, and Proxeed.

 11. Infectious Causes

Although many studies suggest that infections such as gonorrhea, chlamydia, mycoplasma, and ureaplasma are associated with recurrent pregnancy loss, this still remains somewhat controversial.  Regardless, a thorough evaluation of recurrent pregnancy loss includes the performance of cervical cultures designed to detect the presence of these conditions.  Regardless of the culture results, each member of the couple is subsequently treated with antibiotics for at least 10-14 days, as cervical cultures have been demonstrated to be accurate less than 70% of the time.

 

 

References:

http://www.resolve.org/diagnosis-management/infertility-diagnosis/multiple-miscarriages-causes-tests-and-treatments.html

http://rba-online.com/ivf/index.php?Recurrent-Pregnancy-Loss-RPL-23

http://txfertility.com/female-infertility/recurrent-miscarriage/