Recurrent Pregnancy Loss

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Chapter 41 Recurrent Pregnancy Loss


Recurrent pregnancy loss is a profound personal tragedy to couples seeking parenthood and a formidable clinical challenge to their physicians. Spontaneous abortion occurs in approximately 15% of clinically diagnosed pregnancies in reproductive-age women, but recurrent pregnancy loss occurs in about 1% to 2% of this same population.1 Great strides have been made in characterizing the incidence and diversity of this heterogeneous disorder, and a definite cause of pregnancy loss can be established in approximately two thirds of couples after a thorough evaluation.2 A complete evaluation will include investigations into genetic, endocrinologic, anatomic, immunologic, microbiologic, thrombophilic, and iatrogenic causes. Recurrent pregnancy losses may induce significant emotional distress; in some cases intensive supportive care may be necessary. Successful outcomes will occur in more than two thirds of all couples.3


The traditional definition of recurrent pregnancy loss included those couples with three or more spontaneous, consecutive pregnancy losses. Ectopic and molar pregnancies are not typically included. There is no specific classification for those women who have multiple spontaneous miscarriages interspersed with normal pregnancies, nor is it clear whether occult early miscarriages diagnosed by sensitive human chorionic gonadotropin (hCG) assays should be included in these definitions.

Several studies have recently indicated that the risk of recurrent miscarriage after two successive losses is similar to the risk of miscarriage in women after three successive losses; thus, it is reasonable to start an evaluation after two or more consecutive spontaneous miscarriages to determine the etiology of their pregnancy loss, especially when the woman is older than age 35 or when the couple has had difficulty conceiving.3,4 Any loss before 20 gestational weeks is considered a miscarriage. Some authors further divide these into embryonic losses, which occur before the ninth gestational week, and fetal losses, which occur at any time from the 9th gestational week to 20 weeks’ gestation, although there is no developmental phase to justify this distinction. Those couples with primary recurrent loss have never had a previous viable infant; those with secondary recurrent loss have previously delivered a pregnancy beyond 20 weeks’ gestation and then suffered subsequent losses. Other investigators advocate the designation of tertiary recurrent loss to identify those women who have multiple miscarriages interspersed with normal pregnancies.


The main concerns of couples who have had a spontaneous abortion are the cause and the risk of recurrence. In a first pregnancy, the overall risk of loss of a clinically recognized pregnancy is 15%.5,6 The true rate of early pregnancy loss, however, is estimated to be around 50% because of the high rate of losses that occur before the first missed menstrual period. Studies that evaluated the frequency of pregnancy loss, based on highly sensitive tests for quantitative hCG, indicated that the total clinical and preclinical losses in women age 20 to 30 is approximately 25%, whereas the loss rate in women age 40 or more is at least double that figure.7,8 For women who have had one miscarriage, the risk of another loss rises slightly, to 14% to 21%. After two or three miscarriages the rate rises to 24% to 29% and 31% to 33%, respectively.9 The ability to predict the risk of recurrence is influenced by several factors.

Maternal Age

Advancing maternal age is associated with a higher rate of pregnancy loss of both normal and abnormal conceptuses.10,11 This probably reflects poor oocyte quality and reduced endocrine function in this group. In one study of more than 1 million pregnancies, the overall rate of spontaneous abortion was 11% and the approximate rates of clinically recognized miscarriage according to maternal age were 9% to 17% (age 20 to 30), 20% (age 35), 40% (age 40), and 80% (age 45).10


Increasing parity is associated with an increased rate of spontaneous abortion.14 This may be partially explained by the correlation between maternal age and parity.


Genetic Factors

Single gene, chromosomal, X-linked, or multifactorial disorders can result in sporadic or recurrent pregnancy loss.


In translocations, chromosome segments are exchanged between nonhomologous chromosomes. There are two main types of translocation: reciprocal and Robertsonian. In reciprocal translocations, the type of rearrangement results from breakage of nonhomologous chromosomes, with reciprocal exchange of the broken-off segments. Usually only two chromosomes are involved, and because the exchange is reciprocal, the total chromosome number is unchanged. Reciprocal translocations are relatively common and are found in approximately 1 in 500 newborns. Like other balanced structural rearrangements, they are associated with a high risk of unbalanced gametes and abnormal progeny.

Robertsonian translocations involve two acrocentric chromosomes (numbers 13, 14, 15, 21, or 22) that fuse near the centromere region with loss of the short arms. Although a carrier of a Robertsonian translocation is phenotypically normal, there is a risk of unbalanced gametes and therefore unbalanced offspring. The risk of subsequent abortions varies with the type of translocation and the sex of the carrier. Robertsonian translocations are a more homogeneous group, and so the information on them is the most consistent. Studies indicate that when the Robertsonian translocation is maternal, there is a greater risk that the fetus will exhibit an unbalanced phenotype.17

Neri and coworkers found that carriers of these translocations had a 20% to 25% risk of spontaneous abortion. The only exceptions are translocations involving homologous chromosomes. If, for example, both copies of chromosome 22 fuse, the carrier should produce only trisomy 22 or monosomy 22, all of which would abort. Carriers of this type of translocation should therefore have a 100% rate of pregnancy loss, but two unexplained normal offspring from such carriers have been reported.18,19

Endocrinologic Factors

Endocrine factors may contribute to 8% to 12% of recurrent pregnancy loss. Progesterone is essential for successful implantation and maintenance of pregnancy. Therefore, disorders related to impaired progesterone production or actions are likely to affect pregnancy success. These include luteal phase insufficiency, hyperprolactinemia, and polycystic ovary syndrome (PCOS). Other endocrinologic factors associated with increased risk of pregnancy loss include diabetes, thyroid disease, and decreased ovarian reserve.

Luteal Phase Defect

Maintenance of early pregnancy depends on the production of progesterone by the corpus luteum. Between 7 and 9 weeks’ gestation the developing placenta takes over progesterone production. Luteal phase defect is defined as an inability of the corpus luteum to secrete progesterone in high enough amounts or for too short a duration. Abnormalities of the luteal phase have been reported to occur in up to 35% of women with recurrent abortion.30

Several potential mechanisms are thought to give rise to a luteal phase defect: decreased production of progesterone by the corpus luteum, decreased follicle-stimulating hormone (FSH) levels in the follicular phase, abnormal patterns of luteinizing hormone (LH) secretion, decreased response by the endometrium to already-secreted progesterone, and increased prolactin levels. The preponderance of evidence suggests that luteal phase defect is a preovulatory event most likely linked to an alteration in preovulatory estrogen stimulation, which may indicate poor oocyte quality and a poorly functioning corpus luteum.31,32

Classically, the diagnosis is based on results of endometrial biopsy. The endometrium is considered out of phase when the histologic dating lags behind the menstrual dating by 2 days or more. However, there is considerable interobserver and intraobserver variation in the interpretation of the biopsies. Furthermore, the expression of a luteal phase defect is not consistent in affected women, and unaffected women frequently have endometrial histology suggestive of luteal phase defect. Because of these issues, luteal phase defect is diagnosed only when two consecutive biopsies are out of phase. Endometrial biopsy is performed 10 days after the LH surge or after cycle day 24 of an idealized 28-day cycle.

Some authors have advocated the measurement of serum progesterone levels in the luteal phase for the diagnosis of luteal phase defect, with levels below 10 ng/mL considered abnormal.33 However, progesterone levels are subject to large fluctuations because of pulsatile release of LH. Moreover, there is a lack of correlation between serum levels of progesterone and endometrial histology.34 Nonetheless, serum progesterone levels of 10 ng/mL or greater in the midluteal phase of the menstrual cycle are generally utilized to exclude luteal phase defect.

Untreated Hypothyroidism

Untreated hypothyroidism may increase the risk of miscarriage. A recent study of more than 700 patients with recurrent pregnancy loss identified 7.6% with hypothyroidism.35 Hypothyroidism is easily diagnosed with a sensitive thyrotropin test, and patients should be treated to become euthyroid before attempting a next pregnancy. It has also been suggested that thyroid antibodies are elevated in women with recurrent pregnancy loss. A retrospective study of 700 patients with recurrent pregnancy loss demonstrated that 158 women had antithyroid antibodies but only 23 of those women had clinical hypothyroidism on the basis of an abnormal thyrotropin value.36 The presence of antithyroid antibodies may imply abnormal T-cell function; therefore, an immune dysfunction rather than an endocrine disorder may be responsible for the pregnancy losses.

Insulin Resistance

Patients with poorly controlled diabetes are known to have an increased risk of spontaneous miscarriage, which is reduced to normal spontaneous loss rates when women are euglycemic preconceptually.37 Hyperglycemia and vascular complications resulting in compromised blood flow to the uterus may be responsible for the pregnancy loss. It is known that women with PCOS have an increased risk of miscarriage. The mechanism is unknown, but may be related to elevated serum LH levels and high testosterone and androstenedione concentrations, which may adversely affect the endometrium.38 It also may be related to the high prevalence of insulin resistance in these women.39 Testing for fasting insulin and glucose is simple, and treatment with insulin-sensitizing agents may reduce the risk of recurrent miscarriage.40

Elevated Day 3 FSH

Elevated day 3 FSH levels have been associated with decreased pregnancy rates in women undergoing in vitro fertilization (IVF). Although the frequency of elevated day 3 FSH levels in women with recurrent miscarriage is similar to the frequency in the infertile population, the prognosis for recurrent miscarriage is increased with increased day 3 FSH levels.41 Thus, it is speculated that women with recurrent pregnancy loss and elevated day 3 FSH levels may have poor quality oocytes with inherent chromosomal abnormalities. Although no treatment is available, testing should be performed in women over age 35 with recurrent pregnancy loss, and appropriate counseling should follow.


Normal circulating levels of prolactin may play an important role in maintaining early pregnancy. Data from animal studies suggest that elevated prolactin levels may adversely affect corpus luteal function; however, this concept has not been proven in humans.42 A recent study of 64 hyperprolactinemic women showed that bromocriptine therapy was associated with a higher rate of successful pregnancy and that prolactin levels were significantly higher in women who miscarried.43

Anatomic Factors

Anatomic uterine defects are present in 15% to 20% of women evaluated for three or more consecutive spontaneous abortions.2 These anatomic abnormalities can be classified as congenital or acquired. Uterine malformations appear to predispose women to reproductive difficulties, including first- and second-trimester fetal losses, preterm labor, and abnormal fetal presentation.

Congenital Uterine Anomalies

Congenital malformations of the reproductive tract result from failure to complete bilateral duct elongation, fusion, canalization, or septal resorption of the müllerian ducts. Müllerian anomalies were found in 8% to 10% of women with three or more consecutive spontaneous abortions who underwent hysterosalpingography or hysteroscopic examination of their uteri.2,44 Inadequate vascularity, compromising the developing placenta, and reduced intraluminal volume have been theorized as possible mechanisms leading to pregnancy loss.

The most common abnormality associated with pregnancy loss is the septate uterus. The spontaneous abortion rate is high, averaging about 65% of pregnancies in some studies.45 A septum is primarily composed of fibromuscular tissue that is poorly vascularized (Fig. 41-1). This lack of vascularization may compromise decidual and placental growth. Alternatively, a uterine septum may impair fetal growth as a result of reduced endometrial capacity or a distorted endometrial cavity.45 Uncontrolled studies suggest that women who undergo resection of the uterine septum have higher delivery rates than women without treatment. Other congenital abnormalities, such as uterus didelphys, bicornuate uterus, and unicornuate uterus, are more frequently associated with later trimester losses or preterm delivery.

Diethylstilbestrol Exposure

Diethylstilbestrol (DES) is an orally active synthetic estrogen that was introduced in the 1940s for the treatment of recurrent pregnancy loss, premature delivery, and other complications of pregnancy. The use of DES in pregnancy was banned in 1971.46

Uterine abnormalities occur in 69% of women exposed to DES in utero.46 The most common abnormality is a T-shaped uterine cavity (70%). Other abnormalities include a small uterus, constriction rings, and intrauterine filling defects. In addition, 44% of DES-exposed women have structural changes in the cervix, including an anterior cervical ridge, cervical collar, hypoplastic cervix, and pseudopolyp. Women with a history of in utero exposure to DES appear to have a greater risk of adverse pregnancy outcome, including a twofold increased risk of spontaneous abortion and a ninefold increase in ectopic pregnancy rates.47

Acquired Uterine Abnormalities


The primary function of the immune system is to recognize and eliminate potentially pathogenic organisms from the body. To understand how immunologic factors can affect pregnancy, a basic understanding of the normal immune response is required. The immune response has two components: the innate, or nonspecific, immune response and the acquired, or adaptive, immune response.

Autoimmune Factors: Maternal Response to Self

In some instances, there is a failure in normal control mechanisms that prevents an immune reaction against self, resulting in an autoimmune response.53 Autoantibodies to phospholipids, thyroid antigens, nuclear antigens, and others have been investigated as possible causes for pregnancy loss.35 Antiphospholipid antibodies include both the lupus anticoagulant and anticardiolipin antibodies. There is still controversy concerning testing for other phospholipids, but an increasing number of studies suggest that antibodies to phosphatidyl serine are also associated with pregnancy loss.54

Systemic Lupus Erythematosus

Most clinical studies find that pregnancy loss is more common among women with systemic lupus erythematosus (SLE) than among normal women.55 The rate of spontaneous abortions among patients with SLE in one large study was estimated at 21%.56 Nearly three quarters of pregnancy losses appear to occur in the second and third trimesters.57 Most fetal deaths in women with SLE are associated with the presence of antiphospholipid antibodies.55,58 In a study of women with SLE and recurrent pregnancy loss, women with antiphospholipid antibodies had a tenfold increased risk of miscarriage compared to women with SLE but without antiphospholipid antibodies.55 Other factors associated with pregnancy loss in this population include (1) disease activity before conception, (2) the onset of SLE during pregnancy, and (3) underlying renal disease. Women with active SLE should be advised to delay conception until remission is established. Women with moderate renal insufficiency should be advised against pregnancy. Women should also be counseled about the higher rates of preeclampsia and premature delivery with SLE.57

Antiphospholipid Antibody Syndrome

Antiphospholipid antibody syndrome is an autoimmune condition characterized by the production of moderate to high levels of antiphospolipid antibodies and certain clinical features. The presence of antiphospholipid antibodies (anticardioplipin and lupus anticoagulant) during pregnancy is a major risk factor for adverse pregnancy outcome.59 In a large meta-analysis of studies of couples with recurrent abortion, the incidence of antiphospholipid antibody syndrome was between 15% and 20%, compared to about 5% in nonpregnant women without a history of obstetric complications.60 It is not yet understood how antiphospholipid antibodies arise in patients with the syndrome. Genetic factors and infection may play a role. The antibodies generated in patients with antiphospholipid antibody syndrome appear to recognize epitopes on phospholipid-binding proteins, unlike the antibodies that arise following infections such as syphilis and Lyme disease, which recognize phospholipids directly.61

Several mechanisms have been proposed by which antiphospholipid antibodies might mediate pregnancy loss. It appears that different coagulation proteins may be involved in binding to phospholipids, which may explain the predisposition to thrombosis. Antibodies against phospholipids could increase thromboxane and decrease prostacyclin synthesis within placental vessels. The resultant prothrombotic environment could promote vascular constriction, platelet adhesion, and placental infarction.60 Antiphospholipid antibodies appear to interfere with various components of the protein C antithrombotic pathway, including inhibiting the formation of thrombin, decreasing protein C activation by the thrombomodulin–thrombin complex, inhibiting assembly of protein C complex, inhibiting activated protein C activity, and binding to factors Va and VIIIa in ways that protect them from proteolysis by activated protein C.61 Another proposed mechanism is the disruption of the placental antithrombotic molecule, annexin V. The levels of annexin V are reduced in placental villi of women with recurrent pregnancy loss who are antiphospholipid antibody-positive.62 Antiphospholipid antibodies can also recognize heparin and heparinoid molecules and thereby inhibit antithrombin III activity.63 Antiphospholipid antibodies can interact with cultured human vascular endothelial cells with resultant injury or activation.61 A more direct action on the trophoblastic cells has been demonstrated and explains how antiphospholipid antibodies can cause early fetal loss. Antiphospholipid antibodies have been demonstrated to inhibit secretion of human placental chorionic gonadotropin and to inhibit the expression of trophoblast cell adhesion molecules (α1 and α5 integrins, E- and VE-cadherins).64

Antithyroid Antibodies

An increased frequency of antithyroid antibodies (antithyroid peroxidase, antithyroglobulin) have been reported in women with recurrent pregnancy loss. However, if the patient is euthyroid, the presence of antithyroid antibodies does not affect pregnancy outcome.65 Women who have positive antithyroid antibodies and are euthyroid are at an increased risk for hypothyroidism during and after pregnancy. These women should have their thyrotropin level tested during each trimester and postpartum for thyroiditis.66

Alloimmune Factors: Maternal Immune Response to Trophoblast

Implantation is the process by which the embryo is intimately connected with the maternal uterine and blood-borne cells. The implanting embryo possesses paternal antigens and therefore may be rejected as an allograft. However, in most cases, fetal rejection by the maternal immune system does not occur and seems to be prevented by mechanisms not yet defined. Alloimmune factors have been suggested to be associated with recurrent pregnancy loss. HLA sharing was thought to be associated with recurrent pregnancy loss based on a decreased maternal immune response and, thus, decreased production of blocking antibodies. Recent large studies, however, reveal no association between HLA (and HLA-DQα) homozygosity, and recurrent pregnancy loss.68 Other investigators have implicated certain embryotoxic factors, such as tumor necrosis factor (TNF-α) and IFN-δ, identified in the supernatants of peripheral blood lymphocytes from women with pregnancy loss; however, this has not been confirmed by independent studies. Immunophenotypes of endometrial cells from women with recurrent pregnancy loss demonstrate altered NK cell (CD56+) populations. Some have suggested that increased NK cells are associated with pregnancy loss, whereas others have indicated that decreased NK cells are associated with pregnancy loss. None of these findings have been clearly associated with pregnancy loss; thus, there are no definite recommended tests at this time.69 Several theories have been proposed to account for the immune-privileged state of the decidua.

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