Recurrent Miscarriage: Causes, Evaluation, and Treatment

Abstract

Recurrent miscarriage or fetal loss syndrome (also known as fetal wastage syndrome) is characterized by recurrent spontaneous abortion. There are many syndromes associated with recurrent fetal loss, including anatomic anomalies, endocrine/hormonal abnormalities, genetic/chromosomal abnormalities, and blood coagulation protein/platelet defects. Many of these syndromes are treatable, leading to normal term pregnancy, if the clinician is astute and vigorously pursues a thorough evaluation of why the patient has suffered unexplained, spontaneous miscarriages. There is no uniform agreement on how many spontaneous, unexplained miscarriages are needed to diagnose recurrent fetal loss; we generally pursue an evaluation for causation if a women has had 2 or more such events. In this article, we discuss the common reasons for recurrent fetal loss, plus diagnostic procedures to consider in pinpointing the problem, such as cytogenetic studies, blood coagulation protein/platelet tests, hysterosalpingography, sonography, and magnetic resonance imaging. We also describe management strategies that often lead to successful pregnancy outcome when the underlying problem is addressed. For example, in the case of thrombotic defects, a common cause of recurrent fetal loss, we report a 100% success rate in achieving a normal-term delivery among women who took low-dose (81mg/day) aspirin preconception followed by postconception low-dose (5000 units q12h) heparin.

Introduction

Recurrent miscarriage or fetal loss (RFL) syndrome -- also known as fetal wastage syndrome -- is characterized by repeated spontaneous abortion. There are many syndromes associated with RFL, including anatomic anomalies, endocrine/hormonal abnormalities, genetic/chromosomal abnormalities, and blood coagulation protein/platelet defects (see Fig. 1). The exact prevalence of each of these conditions in inducing RFL remains unclear. However, if the clinician is astute and vigorously evaluates the patient with RFL, the causative defects may be diagnosed and treated, often making normal-term pregnancy possible.





Figure 1. Many syndromes associated with recurrent fetal loss include anatomic anomalies, endocrine/hormonal abnormalities, genetic/chromosomal abnormalities, and blood coagulation protein/platelet defects.

Although there is no uniform agreement on how many spontaneous, unexplained miscarriages constitute RFL, we generally recommend assessment for RFL when a woman has had 2 or more such events. When evaluating a patient with RFL, it is important for the clinician to be aware of the etiology and pathophysiology of common causative syndromes, as well as diagnostic procedures and treatment considerations.

Impact and Implications of Chromosomal Abnormalities

Types

Chromosome imbalance caused by the absence or duplication of chromosomal material most often results in spontaneous abortion. In a live birth, chromosomal imbalance generally produces some phenotypic effect, most often congenital anomalies and mental retardation. There are 2 basic types of chromosomal imbalance: aberrations in chromosome numbers (numerical abnormalities) and defects in chromosome structure (structural anomalies). These can be diagnosed by cytogenetic study (karyotype analysis) of virtually any tissue type.

Numerical chromosomal abnormalities (aneuploidies) -- the presence of an extra chromosome (trisomy) or a missing chromosome (monosomy) -- result from segregation errors during cell division: Chromosomes do not divide evenly among daughter cells (nondisjunction) (see Fig. 2). For unknown reasons, trisomies are positively associated with advanced maternal age. Polyploidy refers to the presence of an extra set of chromosomes. Triploidy, for example, usually occurs when 2 spermatozoa fertilize an oocyte, resulting in a zygote that contains 3 sets of chromosomes instead of 2 (see Fig. 3). Numerical abnormalities are sporadic, and they do not usually recur in subsequent pregnancies.




Figure 2. Karyotype of 47,XX+16 (trisomy 16), most common trisomy associated with spontaneous abortion. Recurrence risk for chromosomal anomaly in subsequent pregnancy is 1% or less. (Arrow indicates extra chromosome.)




Figure 3. Karyotype of 69,XXY (triploidy), common finding in spontaneous abortion. Risk for chromosomal anomaly in subsequent pregnancy is not increased significantly.
Structural chromosomal anomalies are different from numerical anomalies in that they consist of a defect in the structure of 1 or more chromosomes. Examples include inversions (part of a chromosome is turned around), rings (a chromosome forms a ring structure), and translocations (parts of chromosomes in the wrong location). Translocations may be reciprocal or Robertsonian. In a reciprocal translocation, pieces from 2 nonhomologous chromosomes have switched places with each other; in a Robertsonian translocation, 2 acrocentric chromosomes -- that is, chromosomes with essentially a single long arm rather than the more normally encountered long and short arms -- are fused together. The acrocentric chromosomes are 13, 14, 24, 15, 21, and 22. In a balanced structural chromosomal anomaly the amount of chromosomal material present is normal, but the configuration is abnormal. An individual carrying a balanced rearrangement would usually not have any phenotypic effect, except for the possibility of impaired fertility and reproduction.

Structural chromosomal abnormalities occur in about 1 of 500 persons. These structural defects may be passed from parent to child; therefore, when a structural anomaly (balanced or unbalanced) is found in a fetus or in an individual, karyotype analysis of parents and possibly other relatives is indicated.

Relationship to Spontaneous Abortion

Chromosomal anomalies are known to be the single most common cause of spontaneous abortion. Historically, 50% of spontaneously expelled abortuses have been thought to be chromosomally abnormal.[1]However, this is probably an underestimate in light of recent improvements in tissue culture techniques, coupled with earlier diagnosis of miscarriage.[2] In spontaneous abortions, the majority of chromosomal anomalies (95%) are numerical. About 60% are trisomies, trisomy 16 being the most common (see Fig. 2).[1] A further 20% are found to have 45,X (Turner's syndrome).[1]Interestingly, approximately 99% of fetuses with 45,X are expelled spontaneously.[3] Another 15% have polyploidy, especially triploidy (see Fig. 3).[1]


In the case of a numerical chromosomal anomaly in a fetus, parental chromosomes are usually normal, so karyotype analysis of the parents is not indicated. The recurrence risk for a chromosomal anomaly following the diagnosis of trisomy in a pregnancy is thought to be about 1%.[1,4]

After diagnosis of a numerical chromosomal anomaly, couples should be counseled about the 1% risk for recurrence of a numerical anomaly, and prenatal diagnosis of the fetus may be considered for any future pregnancies. On the other hand, if a structural chromosomal anomaly is found in a fetus, parental karyotypes are indicated. The presence of a balanced chromosomal rearrangement in a parent would result in an increased recurrence risk for structural chromosomal defects in future pregnancies.

Role of Chromosomal Anomalies in Recurrent Spontaneous Abortion

In up to 7% of couples with at least 2 spontaneous abortions, one partner carries a balanced chromosome rearrangement.[5] The most common of these is a reciprocal translocation in which a segment of chromosome has exchanged places with a segment of a nonhomologous chromosome. When such a rearrangement is present, the chromosomes have difficulty pairing up and dividing evenly during meiosis. As a result, gametes frequently possess an unbalanced amount of chromosomal material (duplications and/or deficiencies). These imbalances are usually lethal to the developing embryo or fetus, causing spontaneous abortion. Sometimes, the pregnancy continues to term, producing an infant with significant congenital anomalies and mental retardation.


When a parent carries a balanced chromosome rearrangement, the chance of having a live birth with an unbalanced chromosome complement is usually about 1% to 15%. The exact risk depends on the specific chromosomes involved, size of the segment(s) involved in the rearrangement, sex of the transmitting parent, family history, and mode of ascertainment. Therefore, it is quite possible that the couple will have healthy children. In fact, Coulam[6] found a higher incidence of chromosome rearrangement in couples who had experienced both recurrent spontaneous abortion and viable pregnancies than in couples with recurrent spontaneous abortion and no viable pregnancies. When 1 parent carries a chromosome rearrangement, the chance of spontaneous abortion is usually 25% to 50%. Empirical and/or hypothetical data are available for predicting the chance of adverse pregnancy outcome for various rearrangements.[1,7]

Relevance of Family History

When a patient presents having had recurrent spontaneous abortions, a detailed family history should be obtained, including information about the partner's family. The family history may provide a clue to the presence of a familial chromosome rearrangement. A history of any congenital anomaly, mental retardation, infertility, spontaneous abortion, or perinatal death is significant because each is characteristic of chromosomal anomaly (see Fig. 4).



Figure 4. (click image to zoom) Family pedigree showing typical features of familial chromosome rearrangement. In this family, husband had mentally retarded sister and brother whose wife suffered 2 spontaneous abortions. Family history is noteworthy, particularly in view of couple's experience having spontaneous abortion and stillbirth with growth retardation. Blood chromosome study of both partners is necessary to rule out translocation or other chromosomal anomaly.

Cytogenetic Studies of Abortuses

In determining the cause of fetal loss, it is useful to conduct a chromosome study on the abortus. Chromosome analysis is indicated in the case of a stillbirth or neonatal death because chromosomal anomalies are found in approximately 6% of these cases.[8] Tissues for cytogenetic studies should be obtained using sterile technique, and they should be delivered immediately to the cytogenetics laboratory in transport medium provided by the laboratory. If such medium is not available, a laboratory technician can provide information regarding the suitability of sterile saline or other solutions, although culture success is compromised. To avoid this problem, it is important to have tubes of frozen, unexpired transport medium onsite.


Tissue specimens that have been frozen or placed in formalin may not be cultured. Tissues suitable for cytogenetic study include placental villi, chorion, amnion, skin, or internal organs such as liver, lung, kidney, or spleen. For early gestation, the entire abortus may be submitted. For later gestation, blood in a sodium heparin tube is also suitable. Submitting several specimen types increases the culture success rate which, even in laboratories with the most experienced staff, is usually no more than 85%.

Cytogenetic Studies of Parents

When a couple has had 2 or more spontaneous abortions or a child with a structural chromosomal anomaly, chromosomal analysis on both partners should be considered. Analysis requires a 5mL to 10mL blood sample in a tube with sodium heparin.


The chance of a balanced chromosome rearrangement in 1 partner of a couple with 2 or more spontaneous abortions is about 7%.[5] Determining the presence of such a rearrangement in a parent is useful because it provides: (1) an explanation for the miscarriages; (2) information about the risk for a live-born child with potentially serious anomalies, as well as the risk for future miscarriages; (3) availability of prenatal diagnosis in a future pregnancy; and (4) information for members of the extended family who may be at risk and may wish to undergo chromosome testing.

Genetic Counseling

Couples in which 1 partner is found to have a chromosomal rearrangement may benefit from genetic counseling. Counseling should include: (1) an explanation of the findings; (2) associated risks for miscarriage and live birth with phenotypic anomalies; and (3) a discussion of reproductive options, including prenatal diagnosis (amniocentesis or chorion villus sampling), donor insemination (if the husband is the carrier) or egg donor (if the wife is the carrier). Implications for the extended family would also be discussed, and assistance would be provided in informing relatives.


Genetic counseling is best provided before the next pregnancy, so all options may be explored and appropriate planning may be instituted. Although a minority of couples elect not to have biologic children in this situation, the majority are relieved to find out that the chance of having a healthy child is high. Genetic counselors can be located through the National Society of Genetic Counselors.

Blood Coagulation Protein or Platelet Defects

The coagulation protein and platelet defects associated with fetal wastage include factor XIII[9] and factor XII[10] defects; dysfibrinogenemia[11]; antiphospholipid syndrome,[12] including both anticardiolipin antibodies (ACLA) and lupus anticoagulant (LA); plasminogen defects[13]; other fibrinolytic system defects, such as elevated plasminogen activator inhibitor type 1 (PAI-1) or low-tissue plasminogen activator (t-PA)[14,15]; congenital protein S defects; and sticky platelet syndrome.

Factor XIII defects, as well as most cases of dysfibrinogenemia or other hereditary or acquired hemorrhagic defects, lead to inadequate fibrin-induced implantation of the fertilized ovum into the decidua. However, antiphospholipid syndrome, plasminogen defects, fibrinolytic system defects, some cases of dysfibrinogenemia, and other hypercoagulable blood protein and platelet defects are associated with thrombosis of the early placental vessels, precluding viability of the implanted ovum or fetus. It may be postulated, however, that any blood protein or platelet defect associated with hypercoagulability and thrombosis could be associated with placental vascular thrombosis and recurrent fetal loss.[16]

The differential diagnosis of RFL due to blood coagulation protein or platelet defects includes the occurrence of 2 or more unexplained, spontaneous abortions (usually in the first trimester) and a high index of suspicion based on clinical judgment and awareness of the syndrome, followed by appropriate clinical and laboratory evaluation. We have previously reported our experience, including identification and management of women who have had RFL due to blood protein or platelet defects.[16]

Evaluation of Patients with RFL Suspected to Have Blood Protein or Platelet Defects

Given that about 50% to 60% of patients with recurrent miscarriages harbor a coagulation defect and that identification of the defect, followed by appropriate therapy, will lead to normal-term delivery in 98%, the cost of evaluation (about $1200) can be justified. To contain costs of evaluation, patients who are suspected of having blood protein or platelet defects should be evaluated in 2 stages. Stage I consists of a complete history and physical examination, a routine complete blood count, and a panel of those blood protein and platelet defects commonly associated with RFL. If the first panel of blood protein and platelet defect tests is normal, a second panel (stage II) should be considered, consisting of those blood protein defects thought to be more rarely associated with RFL.[16]

Based on our prevalence studies (Table I),[16] a list of stage I blood-protein and platelet-defect assays was generated. A complete outline of panel I and panel II defect assays may be found in Table II.[17] If all tests in panel I are negative, panel II assays should be considered. All abnormal hemostasis results should be repeated at least once for confirmation. Preferred methodologies for these assays are discussed elsewhere in the literature.[16]

 

Treatment Considerations

All patients found to have a blood-protein or platelet defect associated with recurrent fetal loss caused by hypercoagulability and thrombosis (thrombosis/vasculitis) of placental vessels are treated preconception with low-dose aspirin at 81mg/day. The aspirin is initiated immediately upon (1) diagnosis of recurrent fetal loss; (2) association with a blood protein/platelet defect related to thrombosis; and (3) desire for subsequent pregnancy. To inhibit coagulation factor Xa, which can lead to placental thrombi during pregnancy, a fixed low dose of subcutaneous porcine heparin at 5000 units every 12 hours until term is added to the daily aspirin regimen immediately postconception.[16]

To make administration more comfortable for the patient, the injection volume of heparin should be small (20,000 units/mL), with a high drug concentration. Patients must be instructed as to the proper methods for self-administration of subcutaneous heparin. Both aspirin and heparin are used to term.

Following delivery, patients harboring a defect associated with hypercoagulability and thrombosis usually require ongoing antithrombotic therapy of some type. Therapeutic options depend on the nature of the thrombotic defect and on the patient's history, if any, of thrombosis.[16] For patients placed on heparin, the plasma heparin levels are monitored by heparin anti-Xa assay.[16]

Recurrent fetal loss due to blood-protein or platelet defects may come about by 2 mechanisms: disorders associated with either a hemorrhagic tendency or a thrombotic tendency.

Hemorrhagic Defects

Recurrent fetal loss associated with hemorrhagic disorders comes about due to interference with adequate fibrin formation, thereby disrupting implantation of the fertilized ovum into the uterine lining. The hemorrhagic defects associated with recurrent fetal loss include factor XIII, factor X, factor VII, factor V, and factor II (prothrombin) deficiencies, as well as fibrinogen defects including afibrinogenemia and those dysfibrinogenemias associated with hemorrhage. All of these defects are rare; management is generally plasma-substitution therapy.

Thrombotic Defects

The thrombotic defects associated with fetal wastage are quite common and are due to thrombosis of early placental vessels (Fig. 5). Peak fetal loss occurs in the first trimester, but loss also occurs in the second and third trimesters. The thrombotic hemostasis defects associated with recurrent fetal loss include lupus anticoagulants and anticardiolipin antibodies (these 2 comprise the antiphospholipid syndromes associated with recurrent fetal loss),[18,19] factor XII deficiency, dysfibrinogenemias associated with thrombosis, protein C deficiency, antithrombin deficiency, heparin cofactor II deficiency, and fibrinolytic defects (plasminogen deficiency, tissue plasminogen activator deficiency, and elevated plasminogen activator inhibitor type 1).[14,15]



Figure 5. Multiple placental thrombi, as in this placenta from woman with antiphospholipid syndrome, is commonly associated fetal wastage.

Antiphospholipid syndrome is the most common thrombotic defect leading to RFL. A variety of treatment programs have been advocated for this syndrome. However, a difficulty in evaluating these regimens relates to the study methodologies: Some studies have primarily addressed patient populations with secondary antiphospholipid syndrome and fetal wastage (in particular those with underlying systemic lupus erythematosus or other autoimmune disorders), whereas only a few have addressed primaryantiphospholipid syndrome. Primary antiphospholipid syndrome is at least 10 times more common in RFL than secondary antiphospholipid syndrome.


Fetal wastage associated with hemorrhagic disorders is likely to result from interference with adequate fibrin formation for implantation of the fertilized ovum into the uterine lining. For this reason, we choose not to treat vigorously with preconception antithrombotic therapy but rather with low-dose aspirin at 81mg/day. In contrast, Sher and colleagues[20]recently reported the successful use of preconception low-dose heparin for in vitro fertilization techniques. They continue to recommend caution, however, advocating low-dose aspirin as the preconception antithrombotic therapy of choice.

The postconception addition of fixed low-dose porcine mucosal heparin at 5000 units every 12 hours is empirical, as higher doses are associated with bleeding and a lower success rate. However, even lower doses might suffice. We do not advocate using corticosteroid therapy in patients with RFL as the result of antiphospholipid syndrome. This position is based on reports of other researchers and on our preliminary experience administering steroids in conjunction with antithrombotic agents. In patients with antiphospholipid syndrome and other types of thrombosis, corticosteroid use may lower antiphospholipid antibody titers, but they fail to stop thrombotic events.[18,19,21,22]

A variety of treatment programs have been used for women with antiphospholipid syndrome (anticardiolipin antibodies or lupus anticoagulants) and RFL; however, many of these studies have reported on only very small populations, or they have failed to distinguish between primary and secondary antiphospholipid syndrome. Brown[23] reported a 90% failure rate (miscarriage) among untreated women, Perino and colleagues [24] reported a 93% failure rate in untreated women, and Many and coworkers[25] reported a 93% failure rate in untreated patients. Lubbe and Liggins,[26] in a small group of women, noted a successful term pregnancy rate of 80% with use of prednisone and aspirin; a similar success rate with this regimen was noted by Lin.[27] Cowchock and associates[28] observed a 75% success rate with prednisone alone or aspirin alone, but they also noted more undesirable effects in the prednisone-treated population. Landy and colleagues,[29]in a small population, reported a success rate of 90% with either aspirin alone or prednisone alone. However, Many and coworkers[25]noted only a 43% successful term pregnancy rate with aspirin and prednisone. Semprini's team[30]reported only a 14% success rate with prednisone alone.


Several studies have assessed the role of the postconception addition of heparin; however, most have used higher doses than those used in our clinical practice.[16]Rosove and colleagues[31] reported a 93% success rate with dose-adjusted subcutaneous heparin, the mean heparin doses being about 25,000 units/day. Kuttah,[32] in a population of 25 patients, treated with aspirin plus dose-adjusted subcutaneous heparin, noting a success rate of 76% (mean heparin dose of 26,000 units/day). In the study by Many and colleagues,[25] patients treated with prednisone plus aspirin plus heparin at 5000 units twice a day had a better outcome (69%) than those treated with aspirin plus prednisone (43%) or prednisone alone (7%).

Based on the results of our study, it appears that fixed low-dose porcine heparin is more effective than the high-dose, dose-adjusted regimens. This was evidenced by the success rate of 100%, whereby all patients with antiphospholipid-syndrome-induced RFL had normal-term deliveries.[16] It may be that higher doses of heparin contribute to adverse outcomes, such as small periplacental hemorrhages. Parke[33]reported on the combination of low-dose heparin used in conjunction with intravenous immunoglobulin (IVIG). Her success rate for this regimen, however, was only 27%, suggesting that IVIG has little role in antiphospholipid recurrent fetal loss.

In our experience, sticky platelet syndrome (SPS) is the second most common prothrombotic defect contributing to RFL-associated blood coagulation protein/platelet defect. Other common causes include protein S deficiency, tissue plasminogen activator (TPA) deficiency, activated protein C resistance, and type 1 plasminogen activator (PAI-1) defects (Table I). Patients with SPS are treated the same as those with other prothrombotic defects, using preconception low-dose aspirin and immediate postconception addition of low-dose porcine heparin, with both agents being used to term delivery. It is unclear whether heparin is required in SPS patients; however, given the 100% success rate and lack of significant complications with this treatment regimen in our study,[16] it is recommended that heparin be administered to patients with RFL-associated SPS.

Anatomic Abnormalities

Diethylstilbesterol Exposure in Utero

From 1945 to 1971, diethylstilbesterol (DES), a synthetic estrogen, was prescribed for women with threatened or recurrent spontaneous abortion. The use of this agent in pregnant women was then banned in the US. The first evidence of the drug's adverse effects, which occurred a generation removed from the time of administration, was the report by Herbst and Scully[34] in 1970, indicating an increased incidence of vaginal adenosis and clear cell adenocarcinoma of the vagina. There is often relative absence of the vaginal fornices and a "cockscomb" or "hooded" deformity of the anterior cervix. The female offspring of DES-treated women may also have a diminution in the size and capacity of the uterus. The classical appearance of the constricted endometrial cavity on hysterosalpingogram is a "T" configuration. The severity of the abnormality is variable, depending on the dose and duration of administration of the drug during embryogenesis. Women who underwent DES exposure in utero experience an increased likelihood of ectopic pregnancy as well as first- and second-trimester spontaneous fetal losses and preterm labor.

In some cases, the likelihood of second-trimester pregnancy loss resulting from cervical incompetence may be diminished with cervical cerclage. Vigilant assessment of cervical length with transvaginal sonography allows the clinician to identify patients who may benefit from cerclage.[35] When treating patients with DES-induced abnormalities, the surgeon should be liberal in the performance of cerclage. Other than cervical cerclage, surgical intervention rarely improves anatomic abnormality of the DES-affected uterus.

Cervical Incompetence

Painless cervical dilatation during the second trimester, followed by bulging or rupture of the membranes and delivery of an immature fetus, typically suggests cervical incompetence. When cervical dilatation is advanced but membranes remain intact, it may be possible to perform cerclage. In this situation, a tocolytic agent may be necessary; the intervention is technically difficult to perform and frequently fails to salvage the pregnancy.

Often effective, therapeutic leverage may be applied during a subsequent pregnancy. Plans should be made to perform the cerclage by the tenth week of gestation or soon thereafter. Various techniques have been used to close the cervix at the level of the internal os. The most common surgical techniques for cerclage are minor variations of those described by Shirodkar[36] and McDonald.[37] The stitch should be removed by week 37 or upon active labor, to avoid amputation of the cervix. When vaginal fornices are absent and a secure transvaginal cerclage is impossible, a transabdominal cerclage should be considered.[38]

Congenital Müllerian Duct Malformations

The anatomic variations of the müllerian duct malformation are legion. The classic abnormality associated with recurrent second-trimester fetal loss is the septate uterus. The vertical septum extends a variable length from the fundus toward the cervix. The septum may be thick or thin, entirely fibrous or vascular, and partially covered by a layer of endometrium. In addition, the "compartments" into which the uterine cavity is divided by the septum may not be symmetrical. These anatomic variants, as well as the site of embryo implantation, dictate whether the septum might cause first- or second-trimester spontaneous abortion or preterm labor, or whether it will not present a problem.

Symptoms other than fetal loss seldom lead to the detection of müllerian duct malformation. Hysterosalpingogram and sonography usually establish the diagnosis, although on occasion there is difficulty in distinguishing the septate from the bicornuate uterus. Historically, clinicians required that a patient have 2 or 3 miscarriages before offering surgical intervention. In that era, laparotomy was required, and the septum was excised according to the techniques described by Jones or by Tompkins.[39] Both of these surgical procedures necessitated bivalving the uterus. Customary postoperative recommendations included deferring conception for at least several months to ensure complete healing of the uterine incision. It was also suggested that the subsequent delivery be performed by cesarean section.

Today, the management of this malformation is simple incision of the septum with a scissors at hysteroscopy.[40] Routinely, the hysteroscopy is accompanied by laparoscopy to distinguish definitively septate from bicornuate uteri and to ensure that the dissection of the septum is not overzealous. The bicornuate uterus would rarely require surgical intervention to improve obstetric outcome.

In addition to the aforementioned duct malformations, unicornuate and hypoplastic uteri are common. Magnetic resonance imaging (MRI) is most useful in delineating the malformation when the abnormality cannot be precisely discerned by sonogram and hysterosalpingogram.

Leiomyoma

Many women with fibroids (if not the majority) have normal fertility and pregnancies that are without complication. Spontaneous abortion related to a leiomoyoma is the consequence of either the size or strategic location of the lesion. Submucous intracavitary fibroids are the most likely to interfere with successful progression of an early pregnancy. Large intramural lesions that compress the endometrial cavity, thereby altering the blood supply to the implantation site, may also cause early termination of pregnancy. Even very large subserous fibroids are unlikely to cause early disruption of pregnancy in the absence of an unusual event (acute degeneration resulting in an increase in myometrial contractions). Submucous lesions are almost always associated with a history of menorrhagia.


The hysterosalpingogram has been a traditional test to assess compromise of the endometrial cavity by fibroids. Sonography and, in selected instances, hysterosonography are helpful in determining the relevance of fibroids to pregnancy wastage. In exceptional instances, pelvic MRI may be required to define the pathology. Pretreatment with a gonadotropin-releasing hormone (GnRH) agonist is frequently used to reduce the size of the fibroid before surgical intervention; such treatment also may diminish intraoperative blood loss. Large intramural leiomyomas necessitate myomectomy through laparotomy or laparoscopy, depending on the size/location of the tumor and the operative skills/experience of the surgeon. Submucous fibroids are usually best managed with a resectoscope at hysteroscopy.[41]

Intrauterine Synechiae

Intrauterine synechiae are an infrequent cause of spontaneous abortion. Diagnosis is made by hysterosalpingogram or hysterosonography, and lysis of the intracavitary adhesions may be performed under direct vision during hysteroscopy.[42]

Editorial Comment: What Really Causes Recurrent Miscarriage?

I do not subscribe to the authors' apparent belief that more than 50% of recurrent miscarriages are due to coagulation or immunological factors. Any miscarriage is a psychologically, and sometimes physically, devastating event. This is even more the case when miscarriages are recurrent, or when miscarriage follows infertility treatment, and when a woman believes she is near the end of her reproductive life. And unfortunately, the incidence of miscarriage increases with age, from 15% at ages under than 25 years to 35% after age 38. Women treated for infertility with clomiphene and human menopausal gonadotropin typically have a miscarriage rate of 25%, which although high is probably no higher than in spontaneously pregnant infertility patients of similar age.[1]

The consensus among physicians about when to begin evaluation of recurrent miscarriage has changed, in part due to the older age of their patients, from after the third or fourth miscarriage to after the second miscarriage, as the authors indicate. Actually, the largest increase in occurrence of miscarriage comes after 1 miscarriage, rising from 13% with no previous miscarriage to 23% after 1 miscarriage, to 29% after 2 miscarriages, and to 33% after 4 miscarriages.[2] For this reason, many physicians believe that chromosome analysis should be performed on the products of conception, obtained by dilatation and curettage, in the first pregnancy in which embryo or fetal demise occurs rather than on the parents after several miscarriages have already occurred.

However, the percentage of miscarriages in which a chromosome abnormality is detected decreases from 70%-80% for a first miscarriage to 40%-50% after 3 or more miscarriages. Therefore, 50% of recurrent miscarriages may be preventable.

The thesis of the review by Bick and colleagues is that 50% or more of recurrent miscarriages are the result of hematological or immunological causes. The authors describe a series of blood tests -- many of which are unavailable except in a research setting -- that can cost more than $1000.

Many physicians would disagree with this viewpoint. The consensus among most scientists is that only approximately 6% of recurrent miscarriages are due to antiphospholipids or other blood disorders. The importance of immunological causes is also debated by many. Other factors that may be important causes of recurrent miscarriage, such as infection and lifestyle, are not discussed in this article.

Recurrent miscarriage is frustrating to patients and physicians alike. There is an almost uncontrollable urge to find a cause and prescribe treatment. All manners of investigation are welcome, but treatment should be used cautiously when its effectiveness has not been established in randomized controlled studies.

References

1. Gardner RJM, Sutherland GR: Chromosome abnormalities and genetic counseling, 2nd edition. New York, Oxford University Press, 1996, pp 59-190, 248, 313-317.
   
   
2. Wolf GC, Horger EO 3rd: Indications for examination of spontaneous abortion specimens: A reassessment. Am J Obstet Gynecol 173(5):1364-8, 1995.
   
   
3. Lippe B: Turner syndrome. Endocrinol Metab Clin North Am 20(1):121-152, 1991.
   
   
4. Lippman-Hand A: Genetic counseling and human reproductive loss, in Porter IH, Hook EH (eds): Human Embryonic and Fetal Death. New York, Academic Press, 1980, p. 303.
   
   
5. Boue A, Boue J, Gropp A: Cytogenetics of pregnancy wastage, in Harris H, Hirschhorn K (eds): Advances in Human Genetics. New York, Plenum Press, 1985, pp 30-31.
   
   
6. Coulam CB: Unexplained recurrent pregnancy loss: Epilogue. Clin Obstet Gynecol 29(4):999-1004, 1986.
   
   
7. Daniel A, Hook EB, Wulf G: Risks of unbalanced progeny at amniocentesis to carriers of chromosome rearrangements. Am J Med Genet 33:14-53, 1989.
   
   
8. Hsu LYF: Prenatal diagnosis of chromosomal abnormalities through amniocentesis, in Milunsky (ed): Genetic Disorders and the Fetus, ed 3. Baltimore, Johns Hopkins University Press, 1992, p 160.
   
   
9. Duckert F: The fibrin stabilizing factor, Factor XIII. Blut 26(3):177-179, 1973.
   
   
10. Schved JF, Gris JC, Neveu S, et al: Factor XII congenital deficiency and early spontaneous abortion. Fertil Steril 52(2):335-336, 1989.
    
    
11. Mammen EF: Congenital abnormalities of the fibrinogen molecule. Semin Thromb Hemost 1:184-189, 1974.
    
    
12. Scott JR, Rote NS, Branch DW: Immunologic aspects of recurrent abortion and fetal death. Obstet Gynecol 70(4):645-656, 1987.
    
    
13. Sartori MT, Viero M, Boeri G, et al: Thrombotic diathesis in 6 out of 14 new cases of type I plasminogen deficiency. Thromb Haemost 69:1257, 1993.
    
    
14. Gris JC, Neveu S, Mares P, et al: Plasma fibrinolytic activators and their inhibitors in women suffering from early recurrent abortion of unknown etiology. J Lab Clin Med 125(5):606-615, 1993.
    
    
15. Patrassi GM, Sartori MT, Ruffatti A, et al: Fibrinolytic disorders and recurrent abortions: No relationship with antiphospholipid antibodies. Thromb Haemost 69:1271, 1993.
    
    
16. Bick RL, Laughlin HR, Cohen BM, et al: Fetal wastage syndrome due to blood protein/platelet defects: Results of prevalence studies and treatment outcome with low-dose heparin and low-dose aspirin. Clin Appl Thromb Hemost 1:286-292, 1995.
    
    
17. Dahlback B: Inherited thrombophilia: Resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood 85(3):607-614, 1995.
    
    
18. Bick RL, Baker WF: Antiphospholipid and thrombosis syndromes. Semin Thromb Hemost 20(1):3-15, 1994.
    
    
19. Bick RL, Baker WF: The antiphospholipid and thrombosis syndromes. Med Clin North Am 78(3):667-684, 1994.
    
    
20. Sher G, Feinman M, Zouves C, et al: High fecundity rates following in-vitro fertilization and embryo transfer in antiphospholipid antibody seropositive women treated with heparin and aspirin. Hum Reprod 9:2278-2283, 1994.
    
    
21. Bick RL, Baker WF: Anticardiolipin antibodies and thrombosis. Hematol Oncol Clin North Am 6:1287-1299, 1992.
    
    
22. Bick RL, Pegram M: Syndromes of hypercoagulability and thrombosis: A review. Semin Thromb Hemost 20:109-132, 1994.
    
    
23. Brown HL: Antiphospholipid antibodies and recurrent pregnancy loss. Clin Obstet Gynecol 34:17-26, 1991.
    
    
24. Perino A, Barba G, Cimino C, et al: Immunological problems in the recurrent abortion syndrome. Acta Eur Fertil 20:199-202, 1989.
    
    
25. Many A, Pauzner R, Carp H, et al: Treatment of patients with antiphospholipid antibodies during pregnancy. Am J Reprod Immunol 28:216-218, 1992.
    
    
26. Lubbe WF, Liggins GC: Role of lupus anticoagulant and autoimmunity in recurrent fetal loss. Semin Reprod Endocrinol 6:181, 1988.
    
    
27. Lin QD: Investigation of the association between autoantibodies and recurrent abortions. Chinese J Obstet Gynecol 28:674-677, 1993.
    
    
28. Cowchock FS, Reece EA, Balaban D, et al: Repeated fetal losses associated with antiphospholipid antibodies: A collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol 166:1318-1323, 1992.
    
    
29. Landy HJ, Kessler C, Kelly WK, et al: Obstetric performance in patients with the lupus anticoagulant and/or anticardiolipin antibodies. Am J Perinatol 9:146-151, 1992.
    
    
30. Semprini AE, Vucetich A, Garbo S, et al: Effect of prednisone and heparin treatment in 14 patients with poor reproductive efficiency related to lupus anticoagulant. Fetal Ther 4(suppl 1):S73-S76, 1989.
    
    
31. Rosove MH, Tabsh K, Wasserstrum N, et al: Heparin therapy for pregnant women with lupus anticoagulant or anticardiolipin antibodies. Obstet Gynecol 75:630-634, 1990.
    
    
32. Kuttah WH: Heparin plus aspirin (Hep + ASA) is superior to aspirin alone (ASA) for the treatment of recurrent pregnancy loss (RPL) associated with antiphospholipid antibodies. Proceedings of the Annual Meeting of the American College Obstetricians & Gynecologists, 1994. Abstract.
    
    
33. Parke, A: The role of IVIG in the management of patients with antiphospholipid antibodies and recurrent pregnancy losses, in Ballow M (ed): IVIG Therapy Today. Totowa, NJ, Humana Press, 1992, pp 105-118.
    
    
34. Herbst AL, Scully RE: Adenocarcinoma of the vagina in adolescence: A report of seven cases including six clear cell carcinomas (so-called mesonephromas). Cancer 25:745-757, 1970.
    
    
35. Zilianti M, Azuaga A, Calderon F, et al: Monitoring the effacement of the uterine cervix by transperineal sonography: A new perspective. J Ultrasound Med 14:719-724, 1995.
    
    
36. Shirodkar VN: A method of operative treatment for habitual abortion in the second trimester of pregnancy. Antiseptic 52:299, 1955.
    
    
37. McDonald IA: Suture of the cervix for unsuitable miscarriage. J Obstet Gynaecol Br Emp 64:346, 1957.
    
    
38. Novy MJ: Transabdominal cervicoisthmic cerclage for the management of repetitive abortion and premature delivery. Am J Obstet Gynecol 143:44-54, 1982.
    
    
39. Andrews MC, Jones HW Jr: Impaired reproductive performance of the unicornuate uterus: Intrauterine growth retardation, infertility, and recurrent abortion in five cases. Am J Obstet Gynecol 144:173, 1982.
    
    
40. Daly DC, Maier D, Soto-Alber RS: Hysteroscopic metroplasty: 6 years' experience. Obstet Gynecol 73:201-205, 1989.
    
    
41. Neuwirth RS: Hysteroscopic management of symptomatic submucous fibroids. Obstet Gynecol 62:509-511, 1983.
    
    
42. March CM, Israel R: Gestational outcome following hysteroscopic lysis of adhesions. Fertil Steril 36:455-459, 1981.
    
    
43. Speroff L, Glass RH, Kase NG: Clinical Gynecologic Endocrinology and Infertility, ed 5. Baltimore, Williams & Wilkins, 1994, pp 827-829.
    
    
44. Regan L, Owen EJ, Jacobs HS: Hypersecretion of luteinizing hormone, infertility and miscarriage. Lancet 336:1141-1144, 1990.
    
    
45. Clifford K, Rai R, Watson H, et al: Does suppressing luteinizing hormone secretion reduce the miscarriage rate? Results of a randomized controlled trial. Br Med J 312:1508-1511, 1993.

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