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Recurrent Miscarriages

Probably no aspect of infertility is more traumatic than becoming pregnant and losing the baby. And while most women who miscarry do go on to give birth to a healthy baby, infertility specialists are often called in to find out the cause for the recurrent pregnancy loss (RPL) and recommend treatment.

The incidence of pregnancy loss among all women is about 20%. Statistics show that if the first pregnancy ended in miscarriage, the second pregnancy has a similar probability of miscarriage. After two miscarriages, however, the risk rises to 25%-30%. Approximately 3-5% of pregnant couples suffer from recurrent pregnancy loss. Less than 1% will experience 3 or more consecutive miscarriages. For a woman who has had three consecutive miscarriages but no history of live birth, the next pregnancy has a 30-45% chance of ending in miscarriage. Keep in mind, however, that this means she still has better than 60% odds of carrying the next pregnancy to term!.

The American Society for Reproductive Medicine (ASRM) currently recommends that couples who have 2 or more consecutive miscarriages undergo evaluation to determine the reason for the miscarriages. It had long been believed that – unlike “first” miscarriages, of which a little over half are caused by chromosomal abnormalities – recurrent pregnancy loss have other causes. Recent research has demonstrated that when the genetic analysis of the first miscarriage is normal, genetic analysis of the second miscarriage will be normal 70% of the time. Studies have shown that the incidence of chromosomal abnormality in miscarried pregnancies in women under the age of 35 is only 35% as compared with about 50% in older women. Researchers are still debating what causes the remainder. Possibilities include immune system malfunction, hormone imbalances, distortions of the uterine cavity, and pelvic infections. Studies have also linked the use of alcohol, cigarettes, and excessive caffeine consumption to an increased risk of miscarriage.

The risk of miscarriage increases with age, and, in many cases, can be attributed to an abnormal egg. As a woman gets older, the quality of her eggs diminishes resulting, not only in more miscarriages, but also in an increased infertility and genetic abnormalities (such as Down’s syndrome) rates. When a woman seeks medical care for recurrent miscarriages, her doctor will first seek to diagnose the cause for her problem.

What causes recurrent miscarriage?
A specific cause for miscarriage can be identified in only 50 % of cases.
  • Genetic causes
The incidence of chromosomal abnormalities in either spouse is approximately 1-3%. Your doctor may recommend chromosomal analysis for you and your spouse. A genetic study of the miscarriage tissue should be obtained whenever possible.
  • Uterine factors

Fig. 1

Fig. 2

Fig. 3

If uterine fibroids (fig. 1) or polyps (fig. 2) are found, hysteroscopic surgery is advised to correct the problem.

Similarly, if a woman has a uterine septum (a congenital condition in which the uterus is partially divided into two compartments), hysteroscopic surgery can also correct this defect.

Sometimes, scar tissue within the uterine cavity is responsible for the miscarriage (Asherman’s Syndrome). Removing the scar tissue may improve delivery rates.

  • Immunologic factors – Antiphospholipid antibodies (aPL) or Lupus anticoagulant are present in about 15-20% of patients with recurrent miscarriages. Studies have shown that treatment of such patients with aspirin (81mg daily) or heparin improves live birth rates. The treatment has been demonstrated to be successful in about 80% of recurrent miscarriage patients with positive antiphospholipid antibodies or positive Lupus anticoagulant. However, heparin or low dose aspirin treatment of recurrent miscarriage patients without antiphospholipid antibodies has not been shown to be as effective.

  • Hypothyroidism (low thyroid) – The American Endocrine Society defines hypothyroidism as present when the thyroid stimulating hormone is over 2.5µIU/ml. For women with recurrent pregnancy loss and high TSH level (over 2.5), treatment with thyroid medication is advised to keep the TSH level between 1.0 and 2.5µIU/ml. Patients with hypothyroidism should be screened for antithyroid antibodies (ATA) to rule out thyroid autoimmunity which is often seen in Grave’s disease or Hashimoto’s thyroiditis.

  • Low progesterone levels – If blood tests indicate that a woman has “luteal phase defect” (not producing enough of the hormone progesterone to support an early pregnancy), treatment with progesterone (injectable, vaginal tablets or suppositories) may be considered. Another option is HCG injections to increase the production of progesterone from the ovary. If the miscarriage is caused by faulty ovulation, treatment with fertility medications such as Clomiphene citrate (Clomid, Serophene) can restore normal ovulation and may improve your chance of a successful pregnancy. In some patients with ovulatory dysfunction caused by Polycystic Ovary Syndrome (PCOS), treatment with Insulin blocker (Metformin) has been shown to improve ovulation and may also decrease the risk of miscarriages.

  • Advanced reproductive age – has been associated with diminished ovarian reserve and increased rates of miscarriage. After age 40, 30-40% of pregnancies end in miscarriage, most often as a result of an abnormal number of chromosomes in the embryo (aneuploidy).

  • Infectious causes – In some patients a miscarriage can be associated with the presence of an organism called “Ureaplasma”, which can be detected by a simple cervical culture and treated with an antibiotic, such as, Doxycycline.

  • Celiac disease – is an inflammatory disease of the small intestine caused by dietary gluten. Women with this condition have higher risk of miscarriages.

  • Lifestyle factors – tobacco use, alcohol, obesity, excessive caffeine consumption, exposure to environmental toxins.

  • Unexplained recurrent miscarriages – In women with unexplained or unknown cause for the recurrent miscarriages, no specific treatment has been found to be helpful. In a recent randomized placebo-controlled study of 364 women with unexplained recurrent miscarriages, aspirin and low-molecular weight heparin treatment did not improve live birth rates. 54.5% of women given aspirin and heparin had live births. 50.8% of women given aspirin alone and 57% of women given only placebo (sugar pill) had live births. Most importantly, aspirin and heparin therapy can increase the risk of placental abruption and pregnancy loss. The take home message is that there is no proven benefit to this treatment in women with unexplained recurrent miscarriages and that such treatment may increase the risk of pregnancy loss. Treatment with aspirin and heparin should, therefore, be reserved for patient with recurrent miscarriages caused by positive Lupus anticoagulant or antiphospholipid syndrome.

Cervical factor – Incompetent cervix is associated with second trimester pregnancy loss as a result of weakening of the cervical tissue. The treatment involves placing stitches to strengthen the cervix and prevent it from dilating prematurely.

Evaluation for Recurrent Pregnancy Loss
An evaluation for known causes of recurrent pregnancy loss is most often initiated after 2 consecutive pregnancy losses and may include the following:
  • Genetic factors
    • Chromosomal analysis (karyotype) of both partners.
    • Genetic analysis of the miscarriage tissue is very important. When the result is abnormal.
  • Anatomic factors:

    Hysterosalpingogram (HSG), Saline Infusion Sonography (SIS) or hysteroscopy to make sure that there are no uterine abnormalities.

  • Immunologic factors:

    Antiphospholipid antibodies, lupus anticoagulant

  • Endocrine factors:

    Thyroid, prolactin, Hemoglobin A1c

  • Inadequate progesterone level:

    Consider progesterone levels or endometrial biopsy to rule out corpus luteum defect.

  • Infectious causes:

    Culture for Ureaplasma organism

  • Ovarian reserve evaluation:

    Day 3 FSH and Estrogen (E2), AMH, Antral Follicle Count (AFC), Fragile X

    * Currently, there is no indication for routine screening of women with recurrent miscarriages for antinuclear antibodies (ANA). ANA levels are elevated in 20% of reproductive age women. Women with recurrent miscarriages and elevated ANA levels who were treated with low dose aspirin or prednisone did not benefit from the treatment. In fact, they experienced higher rate of obstetrical complications as compared with women who received no such treatment.

    * Looking for sperm defects (Sperm DNA fragmentation) has not been shown to be beneficial for patients with recurrent pregnancy loss.

Treatment of Recurrent Pregnancy Loss
  • Genetic factors:

    If the problem is abnormal parental chromosomal analysis, the couple should seek genetic counseling. Depending on the specific parental genetic disorder, Preimplantation Genetic Diagnosis (PGD) can help reduce the risk of a subsequent miscarriage.

    When genetic studies of previous miscarriage tissues are abnormal, IVF and Preimplantation Genetic Screening (PGS) have been shown to decrease the risk of another genetically abnormal pregnancy and subsequent miscarriage. Typically, the woman undergoes IVF and the embryos are biopsied at the blastocyst stage (5 days after fertilization). Cells obtained from the embryos can be evaluated utilizing newer genetic screening tests such as Comparative Genomic Hybridization (CGH). Only biopsy proven, genetically normal embryos are transferred into the uterus. Such treatment can significantly improve the likelihood of a successful pregnancy.

  • Uterine disorders:

    Hysteroscopic or laparoscopic surgery is advised to remove polyps, fibroids, uterine septum or adhesions.

  • Endocrine factors:

    Levothyroxine is prescribed when the thyroid level is low.

    When the prolactin level is high, a prolactin lowering medication such as Bromocriptine or Cabergoline can be given to restore normal ovulation.

    An elevated level of Hemoglobin A1c is suggestive of high insulin level. A blood sugar lowering medication, such as Metformin, is often prescribed.

  • Immune disorders:

    When the miscarriages are caused by an immune disorder (positive Lupus anticoagulant or positive antiphospholipid antibodies), treatment with heparin and low dose aspirin can increase the odds of a successful outcome.

  • For patient with celiac disease, gluten-free diet is advised before attempting pregnancy.
  • Unexplained recurrent pregnancy loss:

    When there is no explanation for the miscarriages (unexplained RPL), the couple should wait 2 months before trying to conceive again. During pregnancy, beta HCG levels should be monitored and progesterone suppositories are commonly prescribed if the progesterone level is less than 15-20ng/ml until the 12 week of pregnancy. Pelvic ultrasound is performed early in pregnancy and repeated weekly until the 12th week of gestation. With careful followup and supportive care, the live pregnancy rate approaches 75%.

    Leukocyte immunization and Immunoglobulin (IVIG) therapy have been evaluated in patients with recurrent miscarriages. The treatment is expensive and has been shown to provide no significant benefit in preventing further miscarriages. Similarly, natural killer cells (NK) have not been clearly associated with recurrent pregnancy loss. Therefore, testing or for HLA compatibility or increased natural killer cell presence is not recommended at this time.

What can I do to prevent another miscarriage?
  • Keep in mind that even if the cause for your miscarriages is unknown, with supportive care, you have about 70% chance of having a successful outcome with your next pregnancy. Once the pregnancy test is positive, HCG and progesterone level measurements are performed to confirm that the pregnancy is progressing well. If the progesterone level is less than 15-20 ng/ml treatment with progesterone suppositories is advised until the 12th week of pregnancy. Early ultrasound is then scheduled to evaluate the pregnancy. If all is well, weekly ultrasounds are scheduled until week 12 of pregnancy.
  • If the cause for your miscarriage is known, specific treatment can improve your chances for a successful pregnancy.
  • Maintain healthy weight and exercise regularly; avoid caffeine, alcohol and smoking. Consider folic acid supplementation and baby aspirin therapy. Seek support from professionals or family members to help you cope with the emotional difficulties often experienced after a miscarriage.
  • Some patients consider gestational surrogacy (patient’s embryos implanted into another woman’s womb) in cases of unexplained high order recurrent pregnancy loss.
  • If you are over 40 with recurrent pregnancy loss, the problem may be attributed to poor egg quality. In such cases, Donor egg IVF can be considered.

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