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Recurrent Pregnancy Loss

Introduction

Pregnancy loss is a frustrating experience for patients and physicians alike. The process of human conception is extremely complicated compared to other animals, so it is no surprise that many factors are involved with pregnancy loss. Simplistically, an egg is released at the time of ovulation, fertilized in the distal fallopian tube where it travels for several days until it form a blastocyst that will attach specifically to the uterine lining and begin to grow. Anatomic, immunologic, genetic, and hormonal factors may play a role in this process and in pregnancy loss and are evaluated in the work-up.

The following is a review of the potential causes of recurrent pregnancy loss (RPL). First, we will go over some of the basic statistics concerning pregnancy loss. Then, we will review the commonly accepted causes and treatments.

Definitions

Recurrent pregnancy loss has generally been regarded as 3 or more clinical losses. Data on recurrence risks have suggested that the evaluation is appropriate to begin after 2 losses. Clinical losses are termed embryonic if before the 9th gestational week, fetal if after the 9th week but before the 20th weeks. A stillborn is after the 20th week. Miscarriage (medical term = abortion) is loss before the 20th week of gestation. Approximately 25% of pregnancies will have spotting in early pregnancy but 50% will progress to term. Generally, fetal cardiac activity at less than 110 beats per minute is associated with poor prognosis.

Occurrence and Recurrence

Approximately 15% of recognized pregnancies result in loss. This statistic was based upon clinical criteria such as bleeding and passage of tissue. With more sensitive measures, such as serum b-HCG levels the loss rate may be higher. In one study of 197 ovulating women, the overall loss rate was 31% with 1/3 of those not detectable clinically.

The rate of miscarriage increases with maternal age as shown below.

As you can see, the rate of loss increases with maternal age.

Whether a couple has had a live birth may influence the outcome of the pregnancy.

Recurrence risk relative to prior pregnancy events
Prior outcome Prior loss Recurrence (%)
Live born 0 12
1 24
2 26
3 32
4 26
Miscarriage 1 19
2 35
3 47
4 54

These data suggest that couples with a prior successful pregnancy have about a 70% chance of having another successful pregnancy. Only about ½ will have a successful pregnancy if they have not had a prior delivery. Even with 4 miscarriages, there is still approximately and 50% chance to have a successful pregnancy.

Causes of Recurrent Pregnancy Loss

  1. Genetic factors
  2. Anatomic factors
  3. Endocrine factors
  4. Immune factors (auto-immune, allo-immune)
  5. Microbiologic
  6. Environmental factors
  7. Diminished Ovarian Reserve
  8. Folate and Homocysteine levels

The following will summarize the various factors that have been associated with RPL and the outcomes after treatment. Some areas, such as immunologic causes, are actively debated in the scientific community and debate continues concerning the merits of some of the proposed therapies.

1. Genetic factors

Fetal Factors

Many studies have shown that the majority (60%) of all cases of a single miscarriage is due to fetal chromosome abnormalities. The frequency of chromosome abnormalities at 12 weeks is 60%, 45% at 16 weeks, 12% at 20 weeks, 6% at 24 weeks, and 0.5% at term. During the 1st trimester, the autosomal trisomies are most frequent. Humans have 22 pairs of autosomes and a pair of sex chromosomes for a total of 46 chromosomes. A trisomy is an extra autosome chromosome, so that the resulting fetus would have 47 chromosomes instead of 46. Of these, trisomy 16 is most common and is uniformly lethal. Trisomy 21 (Down’s Syndrome) is also common. These occur when all of the chromosomes fail to separate when the egg (most common) is being produced. An egg and a sperm have ½ of the normal complement of chromosomes (23 of 46, and are called haploid). When they join, they form the normal amount required for life. The most frequent single chromosome anomaly seen is a single X chromosome (Monosomy X, or Turner’s Syndrome). Triploidy (3 complete sets of chromosomes, 3n=69) is the next most common. This extra chromosome set may be due to fertilization of the egg by two sperm instead of one. Thus, chromosome number abnormalities are a common cause of pregnancy loss and a chromosome analysis may be performed on the miscarried tissue in order to see if this is the cause of the loss. Most importantly, a couple should know that they did nothing to cause this.

Parental Factors

Parental chromosome abnormalities are an established cause of recurrent pregnancy loss, and the chromosomes of both parents should be evaluated. In patients with RPL, from 5% to 10% may have a balanced translocation. A piece of a chromosome is placed on another chromosome. The parent has the correct total amount of genetic material, it is just ‘shuffled’. The sperm or egg, which have ½ of the parental complement of chromosomes may have this abnormal chromosome. In effect, the resulting offspring is ‘unbalanced’ in amount of chromosome material and may miscarry. Potential treatments may be donor eggs or donor sperm. Now, Pre-implantation Genetic Diagnosis is available to identify embryo with and without these translocations. Only healthy embryos may then be transferred.

Figure 1. Diagram of Balanced Transocation affecting offspring
 

Figure 2. Diagram of 14,21 Robertsonian Translocation affecting offspring

2. Anatomic factors

Abnormalities of the uterus are well established as a cause of pregnancy loss. These abnormalities may be the result of trauma (i.e. scar tissue, Asherman’s Syndrome), or abnormal development. The developmental anomalies include the septate, bicornuate, unicornuate, and didelphys uterus. These may be associated with concurrent urinary tract abnormalities because the internal genital tract (i.e. uterus and fallopian tubes) develop in parallel with the urinary tract during early gestation. Thus, an intravenous pyelogram should be performed to assess the urinary system in patients with uterine anomalies. The different anomalies have, of course, different effects on pregnancy.

The various abnormalities of the uterus may or may not respond to surgery. For instance, resection of a septum dramatically improves outcome compared to surgery for DES exposure or a bicornuate uterus. A septate uterus may predispose to 1st trimester loss while the bicornuate may predispose to a 2nd or 3rd trimester loss. Thus, a thorough evaluation of the uterus is indicated with a hysterosalpingogram or saline infusion sonogram as part of the evaluation of recurrent pregnancy loss.

Outcome of surgical treatment for uterine anomalies

Abnormality Fetal Survival (%)
  Pre Treatment Post Treatment
Unicornuate 0-40 40
Didelphys 65 65
Bicornuate    
   Strassman 30 85
   Circlage 50 90
Septate 25 90
Arcuate 80 80
DES 65 65

3. Endocrine factors

Hormonal factors which result in defective corpus luteum function and diminished progesterone secretion have been postulated to play a role in recurrent pregnancy loss. Some investigators postulate that as many as 20% of patients with three or more pregnancy losses have a luteal phase defect. The defect may be determined by an endometrial biopsy in the late luteal phase which is more than two days out of phase. Once ovulation occurs, the uterine lining undergoes a specific sequence of changes that are detected microscopically and are thought to play a role in the 'implantation window' and in early embryo implantation and development. A serum progesterone in excess of 10 ng/ml is generally associated with a well developed endometrium. In general, a prolactin level, thyroid function tests should be ordered. Patients with Polycystic Ovarian Syndrome (PCOS) have an increased miscarriage rate (30%). This condition should be evaluated as well. A number of studies show that lowering insulin levels in PCOS with metformin (Glucophage) may reduce the risk of miscarriage. The treatments range from progesterone supplementation, clomid, to gonadotropin therapy. There therapies essentially involve production of multiple eggs in a given cycle and this improve the chances for conception and the likelihood to have quality embryos and uterine lining.

4. Immune (Auto-immune) Factors

The first type of immune dysfunction that appears to play a role in recurrent pregnancy loss is the generation of auto-antibodies. The antibodies are directed against ‘self’ antigens. In essence the body is attacking itself. A large amount of data indicate that anti-phospholipid is central to this process.

The antiphospholipid antibody syndrome has clinical and laboratory features as shown below.

Suggested clinical and laboratory criteria for the diagnosis of antiphospholipid antibody syndrome

Clinical Features Laboratory Features
Pregnancy Loss Lupus anticoagulant
    Fetal death
    Recurrent Pregnancy Loss
Thrombosis IgG anticardiolipin antibodies
(< 20 GPL)
    Venous
    Arterial, Stroke
Autoimmune thrombocytopenia
Other IgM anticardiolipin antibodies (<20 MPL)
    Coombs' positive hemolytic anemia
    Levido reticularis

*** Patients with antiphospholipid antibody syndrome should have at least one clinical and one laboratory finding. Lab tests should be positive on two occasions more than 8 weeks apart.

The syndrome is termed primary if there is no apparent underlying disease and secondary when systemic lupus erythematosis (SLE) is present. The most significant antiphospolipid antibodies bind negatively charged phospholipids and are detected in the laboratory by determing the lupus anticoagulant activity and anticardiolipin antibodies. Interestingly, the syndrome is characterized by a pro-coagulant (i.e. increased clotting of blood in vessels) in the patient, but a prolongation (i.e. decreased clotting time) in the test tube. The tests that are typically used are prolonged activated partial thromboplastin time (aPTT), dilute Russel Viper Venom Time (dRVVT), and Kaolin Clotting time (KCT). If these times are prolonged, the lupus anticoagulant inhibitor is present . Normal plasma will not correct this. If normal plasma corrects this, a search is begun for a clotting factor deficiency, such as Protein S, Protein C, or Anti-thrombin III. These predispose patients to blood clots, especially when they are pregnant. Anti-cardiolipin antibodies are measured using an ELISA assay. Some investigators have examined other antibodies including anti-nuclear antibodies, as well as ‘panels’ including other phospholipids, nucleotides, and histones. These are not, at present, routine and should be considered investigational. Approximately 15% of patients with anti phospholipid antibody syndrome have have recurrent pregnancy loss.

The treatment options have included steriods to suppress the immune system, aspirin and heparin to decrease clotting, and intravenous gamma globulin. (IVIG). While a detailed review of this topic is beyond the scope of this review, some investigators favor mini aspirin with daily heparin(10,000 IU – 20,000 IU daily) in divided doses. Live birth rates have generally exceeded 70% with this regimen.

Allo-immune association

Alloimmunity refers to immunological differences between individuals of the same species. The embryo is immunologically distinct from both parents. The theory implies that the maternal immune system must be suppressed. This is by far the most controversial topic relating to immunologic pregnancy loss. The proposed therapies are not without potential risk. In theory, pregnancy loss may be due to the absence of dissimilarities between paternal and maternal (i.e. HLA sharing). Thus the immune system of the mother would not recognize the fetus as different and the resulting unregulated immune system would destroy the fetus. Another theory is that blocking antibodies are required for normal pregnancy. The assumption was that a measurable factor must be present in serum, presumably an antibody that protects from fetal loss. This theory was disproved when it was found that 40% of women with successful reproductive histories do not make these blocking factors and also that patients totally incapable of antibody secretion can have a successful pregnancy. Leukocyte antibody detection assays, mixed lymphocyte cultures, and HLA typing are of no use in detecting patients at risk for pregnancy loss. Immunophenotyping is controversial as well. Treatments have included immunizing the woman with he husband’s white blood cells. Randomized studies have shown little or no benefit. Studies have found that as few as four to as many as 167 women would need to be immunized in order to achieve one additional live birth. Adverse effects include transfusion reactions, auto-immunity, RBS and platelet sensitization, infection difficulty in obtaining donor organs if needed. IVIG is costly ($7000 - $10000), and may cause hypotension, nausea, headache. Additionally, blood from approximately 150 donors is needed to obtain one vial of IVIG. In summary, there are many controversies regarding the diagnosis and potential treatment of this allo-immunity.

5. Microbiologic

Maternal infections with a wide variety of organisms have been linked to pregnancy loss. These include Mycoplasma, Ureaplasma, Group B Streptococci, Treponema palladium, Toxoplasmosis, and viruses such as rubella, CMV, herpes, and Coxsackie virus. Much interest has centered on Mycoplasma and Ureaplasma, but no cause and effect relationship has been proven.

6. Environmental Factors

Environmental factors alcohol, smoking , drugs (i.e. methotrexate, isotretinoin) have been implicated in pregnancy loss. Controversy exists if caffeine plays a role.

7. Diminished Ovarian Reserve and Recurrent Pregnancy Loss

The increased miscarriage rate as women age is likely due to the age related factors in the eggs. One method to assess ovarian function is with a cycle day #3 FSH level. As women age, the FSH level increases. The higher the FSH (>15 mIU/ml) on day #3 of the cycle the lower the chance of conception. A recent study examined elevated cycle day #3 FSH levels in women with recurrent pregnancy loss. They noted in patients with unexplained loss nearly 60% had elevations in FSH and/or estradiol. This was not dependent on the woman's age, parity, or the presence of infertility. A clomid challenge test is often used to assess ovarian reserve. This is shown below.

An elevation of FSH on day #3 or day #10 is associated with diminished ovarian reserve and is considered a poor prognostic sign.

8. Folate deficiency and elevated homocysteine

Recent studies have examined the relative risk of recurrent pregnancy loss in patients with folic acid deficiency and elevated homocysteine. These two nutrients are important for metabolism. Years ago, it was found that drugs which blocked folic acid metabloism led to pregnancy loss, thus an association appears to exist between low folate and pregnancy loss. Homocysteine and folate metabolism are inter-related. The risk of recurrent pregnancy loss was found to be 3 fold higher in patients with elevated homocysteine levels and low folate levels. It was suggested that folate supplementation may decrease the risk of miscarriage.

9.  Inherited hypercoagulable states

Pregnancy is a hypercoagulable state. This means that blood clots are more likely to occur in pregnant patients than non-pregnant patients. Decreased blood flow secondary to these clots may cause complications for the mother and fetus. Pregnancy increases clotting factors that are produced by the liver which may play a role. Over the past several years, studies have examined several inherited blood clotting factors that may be involved with and increase in maternal venous thromboemboli and pregnancy complications such as intra-uterine growth retardation (IUGR), fetal demise after 20 weeks gestation, preterm delivery before 36 weeks gestation, preeclampsia. Recurrent pregnancy loss or even multiple failed IVF cycles may potentially be an indication for testing these factors. It should be noted that there are very few well designed controlled studies with the factors to be discussed below. The treatment may include anticoagulation with heparin or some other medication which is not without risk, thus it is important to discuss these treatments with your physician.

Genetic tests for Factor V Leiden, the mutation 4G4G in plasminogen activator inhibitor-1 and the G20210A prothrombin gene mutation have been studied in patients with pregnancy and venous thromboembolism and pregnancy complications. Anti-thrombin III, Protein C and Protein S deficiency may be tested and in some studies was shown to associated with these pregnancy complications. The methytetrahydrofolate reductase (MTHFR) gene mutations C677T and A1298C (often associated with increased serum homocysteine levels) may be associated with pregnancy complications as well as neural tube defects and malformations.

 

 

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