Chapter 41 Recurrent Pregnancy Loss

Anne S. Devi Wold, Aydin Arici, William H. Kutteh

INTRODUCTION

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

DEFINITION OF PREGNANCY LOSS

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.

RECURRENCE RISK

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

The Cause of Pregnancy Loss

The specific cause of pregnancy loss affects future outcomes. For example, carriers of balanced translocations 13:14 have a 25% risk of spontaneous abortion. The carriers of 21:22 translocation almost invariably miscarry. Women with submucosal leiomyomas have a 70% chance of recurrent loss if uncorrected.

Pregnancy Outcome

Although the risk of miscarriage increases with each successive pregnancy loss, a pregnancy ending in a live birth reduces the risk of miscarriage in the subsequent gestation.^12,¹³

Parity

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.

Gestational Age

The gestational age at the time of pregnancy loss should be considered in determining both the etiology of the loss and risk of recurrence. The recurrence risk increases as gestational age at the time of loss increases.^11,¹⁵

History of Oligomenorrhea

In one study, a menstrual cycle longer than 34 days was the most important predictor for a pregnancy loss.¹³

ETIOLOGIES OF RECURRENT PREGNANCY LOSS

Genetic Factors

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

Several authors have found the skewed X-inactivation pattern in phenotypically normal women with recurrent pregnancy loss.^27,²⁸ Others have also found a statistically significant increase in the spontaneous abortion rate among family members who carried the skewed X trait.²⁹ Presumably these women have an X-linked mutation or germline mosaicism.

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.

Hyperprolactinemia

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.

Figure 41-1 Hysteroscopic septum division with scissors. Notice the avascular tissue of the septum.

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

Intrauterine Adhesions

Intrauterine trauma resulting from vigorous endometrial curettage or postabortion endometritis is a common instigator for the development of adhesions. Intrauterine adhesions (synechiae) are an acquired uterine defect that has been associated with recurrent miscarriage. The severity of adhesions may range from minimal to complete ablation of the endometrial cavity. The term Asherman’s syndrome is often used to describe intrauterine adhesions associated with amenorrhea. These adhesions are thought to interfere with normal placentation and are treated with hysteroscopic resection.

Intrauterine Masses

Intrauterine cavity abnormalities, such as leiomyomas and polyps, can contribute to pregnancy loss. There are several hypotheses concerning how leiomyomas may be associated with recurrent pregnancy loss. Depending on the leiomyoma size and location, it may partially obliterate or alter the contour of the intrauterine cavity, providing a poorly vascularized endometrium for implantation or otherwise compromising placental development. Uterine leiomyomas and polyps may also act like an intrauterine device (IUD), causing subacute endometritis. Until recently, it was felt that only submucous leiomyomas should be surgically removed before subsequent attempts at pregnancy. However, several recent studies investigating the implantation rate in women undergoing IVF have clearly demonstrated decreased implantation with intramural leiomyomas in the range of 30 mm.⁴⁸ When smaller leiomyomas are identified, it is unclear if myomectomy is beneficial.⁴⁹

Incompetent Cervix

Cervical incompetence can be considered an acquired uterine anomaly that is associated with recurrent pregnancy loss. The diagnosis of cervical incompetence is based on the presence of painless cervical dilation resulting in the inability of the uterine cervix to retain a pregnancy. Cervical incompetence commonly causes pregnancy loss in the second trimester. It may be associated with congenital uterine abnormalities, such as septate or bicornuate uterus. Rarely, it may be congenital following in utero exposure to DES.⁴⁷ It has been reported that trauma to the cervix from conization, loop electrosurgical excision procedures, dilation of the cervix during pregnancy termination, or short cervical lengths on ultrasound increase the risk of cervical incompetence.⁵⁰

IMMUNOLOGIC FACTORS

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.

Innate and Acquired Immune Responses

The innate immune response provides a rapid but relatively weak and nonspecific response. This represents the body’s first line of defense against pathogenic invasion. It is mediated by nonspecific soluble products (lysozyme, complement, and acute phase proteins) as well as host defense cells such as macrophages and natural killer (NK) cells. NK cells are large granular lymphocytes that are not of T-cell or B-cell lineage. The function of NK cells is direct killing of virus-infected cells and production of cytokines, resulting in a rapid but relatively nonspecific response to infection. They may also be important in polarizing T cells toward Th-1 responses via production of interferon-γ (IFN-γ).

Acquired or adaptive immune responses are antigen-specific and lead to memory, but require 4 to 7 days to be effectively generated. T cells and B cells and a small proportion of NK cells largely mediate these responses. B cells differentiate in bone marrow. T and B cells occur in tissues in approximately equal numbers. T cells are responsible for cell-mediated immunity and are essential for B-cell function.⁵¹

Human Leukocyte Antigens

T cells recognize processed antigenic peptides presented in association with cell-surface molecules called human leukocyte antigens (HLA), which are products of a group of genes in the major histocompatibility complex (MHC), located on chromosome 6 in humans. HLA molecules are cell-surface glycoproteins that are present on the surface of nearly every cell in the human body and are important in the defense against intracellular pathogens, such as viral infection and oncogenic transformation. They constitute the tissue type of an individual. T cells originate from the bone marrow and migrate to the thymus, where they mature. During this process only T cells that have a low binding affinity to HLA and self-peptides are allowed to mature into CD4+ and CD8+ T cells. In summary, only T cells that can recognize nonself but will not react to self are chosen. T cells recognize antigens via the T-cell receptor on the surface.

T-helper Lymphocytes

T cells produce a range of cytokines following an immune challenge. The type of cytokine determines their differentiation into T helper 1 (Th1) and T helper 2 (Th2) lymphocytes. For example, Th1 lymphocytes secrete interleukin-2 (IL-2) and IFN-γ, creating a pro-inflammatory environment. Conversely, Th2 lymphocytes secrete cytokines, such as IL-4 and IL-10, that are predominantly involved in antibody production following an antigenic challenge. The actions of the two types of lymphocytes are intertwined, acting in concert and responding to counterregulatory effects of their cytokines. Hormones have a powerful effect on this action. During their reproductive years, women are more likely to develop a Th1 response after challenge with an infectious agent or antigen, except during pregnancy, when a Th2 environment prevails.⁵²

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