Early Pregnancy Loss and Fetal Death
Erol Arslan
Kellie Woodfield
David Ware Branch
Introduction and Definitions
The desire to have children is biologically paramount, and yet human reproduction is somewhat inefficient. In a general obstetric population, 20% of pregnancies fail after being evident only by transient elevation of human chorionic gonadotropin before or near menses.1 Another 10% to 12% fail as either pre-embryonic or embryonic losses,1 and approximately 0.5% to 1% of ongoing pregnancies are lost as fetal deaths at or beyond 10 weeks but before the 20th week.2
Much of the existing literature includes pre-embryonic, embryonic, and fetal losses grouped together by defining miscarriage or pregnancy loss as any loss prior to 20 weeks’ gestation—this is the definition adapted by the World Health Organization and the Centers for Disease Control and Prevention. We believe that a more precise characterization of the details of pregnancy loss is valuable for both clinical and investigative reasons. Although various definitions of pregnancy losses are in use, a current and practical categorization that also recognizes distinct, albeit overlapping, periods in embryo-fetal development is shown in Table 1.1.3
In this chapter, the term early pregnancy loss (EPL) will be used to refer to clinically recognized pregnancies that fail prior to 10 weeks’ gestation—in clinical practice, these are predominantly pre-embryonic and embryonic pregnancy losses but may include peri-implantation losses. We will group early fetal death (between 10 and 15 6/7 weeks) and late fetal death (between 16 and 19 6/7 weeks) together. Fetal death resulting in stillbirth at or beyond 20 weeks is covered in Chapter 4, and cervical insufficiency is covered in Chapter 48. We recognize that the above categorizations of pregnancy loss are somewhat arbitrary and that many of the etiologies for loss within each category overlap with those of others. However, a formal categorization of the gestational age of the death of the conceptus informs counseling and underpins meaningful research.
In this chapter, we assume that most publications about recurrent pregnancy loss or recurrent miscarriage refer predominantly to EPLs in which the viability of the conceptus has failed prior to 10 completed weeks’ gestation, that is, pre-embryonic or embryonic pregnancy loss.
Sporadic Early Pregnancy Loss
Sporadic early pregnancy loss (SEPL), or sporadic miscarriage, is the occasional, nonconsecutive pregnancy loss that occurs in a woman who has (or will have) her desired number of children. It is difficult, if not impossible, to capture the true incidence of SEPL due to the wide array of definitions in the literature, as well as variations in the effort taken to diagnose the event, particularly because up to two-thirds of sporadic miscarriages may be clinically silent. Nevertheless, reasonable estimates suggest that up to 30% of pregnancies in otherwise healthy women are lost after implantation.4
The clinical presentation of SEPL is classified into several well-known (though sometimes ill-defined) categories: threatened abortion, inevitable abortion, incomplete abortion, missed abortion known as early pregnancy failure, complete abortion, and septic abortion (Table 1.2).
The etiology of SEPL can be divided into fetal, maternal, and paternal factors. Fetal factors, primarily genetic, play a prominent role in the etiology of SEPL, with aneuploid abortions occurring in an estimated 50% to 70% of cases.10 The incidence of aneuploid abortions decreases with advancing gestational age, accounting for less than one-third of second-trimester losses and 5% or less of third-trimester losses.11
Table 1.1 Suggested Classification of Pregnancy Loss by Periods in Embryo-Fetal Development | ||||||||||
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Chromosomal abnormalities responsible for SEPL are most often the result of errors in maternal gametogenesis; errors in paternal gametogenesis occur in only 5% of cases.11 The most common chromosomal abnormality in sporadic miscarriages is single autosomal trisomy, which account for well over half of the abnormal karyotypes in SEPL.12 This is usually the result of isolated nondisjunction or the failure of homologous chromosomes to separate. Among these, trisomy 16, 22, and 15 account for over one-third of the single autosomal trisomies.13 Other abnormal karyotypes include X monosomy, autosomal monosomy, triploidy, tetraploidy, and chromosomal structural abnormalities such as balanced and unbalanced translocations.12 Autosomal monosomy, or the presence of an unpaired, nonsex chromosome, is incompatible with life. Triploidy pregnancies frequently abort early and are associated with molar gestations. Tetraploidy, or the presence of two extra sets of chromosomes, also abort early.14,15
Table 1.2 Types of Spontaneous Abortion by Clinical Presentation | ||||||||||||
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A wide array of maternal factors also contributes to a tendency for SEPL.11 Age plays particularly prominent role; the incidence of abortions, both aneuploid and euploid, significantly increases after age 35 years. Endocrine abnormalities, most notably insulin-dependent diabetes, are associated with an increased risk of SEPL. Other less common
contributing factors are frank intrauterine infections (infrequent), environmental factors such a radiation exposure in doses used to treat malignancy, and the presence of an intrauterine device (IUD) (associated with septic abortions). Paternal factors are generally less studied and, when present, likely arise from chromosomal abnormalities found in sperm.
contributing factors are frank intrauterine infections (infrequent), environmental factors such a radiation exposure in doses used to treat malignancy, and the presence of an intrauterine device (IUD) (associated with septic abortions). Paternal factors are generally less studied and, when present, likely arise from chromosomal abnormalities found in sperm.
Recurrent Early Pregnancy Loss
Recurrent early pregnancy loss (REPL), most commonly defined as the loss of two or more clinically recognized pregnancies, is one of the most common reproductive health problems. It is estimated to occur in up to several percent of couples desiring to have a family, and approximately 0.5% to 1% of such couples suffer three or more consecutive REPLs.16 The incidence of REPL varies according to a number of factors, including maternal age, number of prior EPLs, and self-selection factors.17,18,19 The rate of miscarriage per recognized conception rises in women above age 35 years, owing in part to increasing rates of aneuploidy associated with older oocytes.17
In the majority of couples, the etiology of REPL is very likely multifactorial, much like many medical conditions. Many contributing factors are still poorly understood, whereas others, such as advanced maternal age and number of prior pregnancy losses, are well-documented but not modifiable. In most couples with REPL, an identifiable, dominant etiologic factor amenable to evidence-based treatment will not be found. Given the frustration and anxiety associated with this reality, some couples will seek unproven, often costly, evaluations and remedies such as heparin agents, low-dose aspirin (LDA), prednisone, and in vitro fertilization and preimplantation genetic screening (IVF/PGS).20,21 Fortunately, most couples with REPL will have one or more successful pregnancies. Best clinical practice calls for a fundamental understanding of the current status of REPL and an evidence-based approach to evaluation and management.
Known or Suspected Etiologic Factors for REPL
In well over 50% of couples seeking consultation for REPL, a dominant, credible cause for pregnancy losses will not be found. Given this reality, our initial approach is to advise the couple that REPL is regarded by most experts as multifactorial in nature. We mention that advancing maternal age and the number of prior losses are among the factors associated with REPL and that professional guidelines recommend evaluations that we will complete whenever possible.
Lifestyle and Environmental Factors
Whether maternal smoking or alcohol consumption is associated with REPL is uncertain, although each has been associated with SEPL in retrospective studies.22 One retrospective, case-controlled study found that an estimated caffeine consumption of more than 150 mg/d was associated with REPL.23 General physical activity levels have not been associated with REPL and are not linked to sporadic miscarriage.
Obesity (body mass index [BMI] > 30 kg/m2) is associated with REPL, with a recent systematic review noting an odds ratio (OR) of 1.75 (95% confidence interval [CI] of 1.24-2.47).24 In a prospective study, women with obesity were found to have a higher frequency of euploid miscarriages,25 and another study showed that women with obesity having REPL were more likely to have a subsequent miscarriage.26 Although being underweight has been linked to sporadic miscarriage, its relationship to REPL is unknown.
Genetic Abnormalities
While chromosomal abnormalities are an obvious cause of a majority of SEPLs, the rate is modestly lower in REPL.27,28 In support of this, a case-controlled study of 420 abortus specimens showed that significantly more women who were older than 36 years with REPL had euploid products of conception compared to unselected controls.27 If, as most clinicians assume, an abortus with aneuploidy is a sporadic occurrence, its occurrence in a patient with REPL might predict a more favorable outcome in the next pregnancy.29
Emerging evidence suggests that EPLs are, at least in some cases, associated with gain or loss of subchromosomal amounts of genetic material, discernible using such techniques as microarray.30 Given that most of these so-called microdeletions or microduplications are of uncertain pathological significance, they are referred to as copy number changes (CNCs). To be sure, some CNCs are more likely to represent a causative factor in pregnancy loss, including those of large CNC size, deletions (rather than duplications), CNCs including genes
described in the Online Mendelian Inheritance in Man database, and changes not described in data-bases of healthy individuals.
described in the Online Mendelian Inheritance in Man database, and changes not described in data-bases of healthy individuals.
In 3% to 5% of couples with REPL, one of the partners is found to have a balanced chromosomal rearrangement, a figure that is at least several-fold higher than in the general population.31 Most mutations are reciprocal balanced translocations; Robertsonian translocations, sex chromosome mosaicisms, and chromosomal inversions are less commonly found.32 In REPL couples, balanced translocations are more commonly found in the female partner, and it appears that the risk of sub-sequent EPL is increased if the translocation originates from maternal side.33 Moreover, a woman with a first-degree relative with REPL has a two- to sixfold increased risk of REPL herself.33,34 Although there is some evidence that otherwise unexplained REPL is associated with an increased rate of aneuploid sperm and apoptosis,35 the role of such paternal gamete meiotic errors in REPL is uncertain; this is an area that deserves further, more sophisticated study. A case-controlled study investigated the additional risk factors in REPL couples that increased the risk of parental karyotype abnormalities.36 Younger maternal age at second miscarriage, history of ≥3 miscarriages, or having a sibling or parent with >2 miscarriages were found to be associated with higher prevalence of parental karyotype abnormalities.
In addition to numerical and structural chromosomal abnormalities, some single gene disorders are known to be associated with REPL. The most common ones are metabolic disorders and hemoglobinopathies, although they contribute to a very small proportion of REPL cases.32 Skewed X inactivation, a phenomenon of preferential inactivation of one X chromosome instead of random inactivation of either, has been considered as a cause of REPL. One study found that the rate of skewed X inactivation was threefold higher in women with REPL compared to those in the general population,37 while another did not find any association between skewed X inactivation and REPL.38
Uterine Factors
Interpretations of the studies that examine an association between REPL and uterine malformations are limited by variation in the definition of recurrent loss and the use of different malformation classifications systems.39 That said, most experts would accept that uterine malformations are found in 10% to 25% of women with REPL40 with a mean of 12.6% based on results from various studies.22 By comparison, a malformed uterus (including arcuate uterus) is found in approximately 4% to 8% of women seeking gynecologic care for a variety of reasons other than pregnancy loss.39,41 It also has been shown that in women undergoing three dimensional (3D) ultrasound screening for reasons other than pregnancy loss, a history of pregnancy loss was more common in women with uterine malformations than in women with a structurally normal uterus42; a history of first-trimester loss was found in 42% of women with a subseptate uterus and 16% of women with arcuate uterus. The most common malformations found in women with REPL are septate, subseptate, or arcuate anomalies, followed by bicornuate uterus (Figure 1.1). Unicornuate uterus is uncommon.
The cause of REPL in women with uterine malformations may be implantation on a poorly vascularized septum, although this mechanism is supported only by indirect evidence. Whether the degree of uterine cavity distortion, for example, the length of the uterine septum or the reduction in the length of the remaining cavity, is associated with a higher likelihood of pregnancy loss is debatable. Work in murine genetic models suggests that dysregulation of stromal or endometrial tissues might play a role in miscarriages associated with uterine malformations. Murine Hox gene mutants have reproducible uterine anomalies that also are associated with reduced uterine stromal tissue and reduced epidermal growth factor receptor expression.43 Hoxa10 and Hoxa11 genes mutants have
abnormal uterine and/or stromal development, and normal endometrial Hoxa10 expression appears to be critical for implantation in adult mice.44 The possibility that some women with REPL and uterine malformations may be found to have altered gene expression in uterine tissues is intriguing, and variants of uncertain significance have been found in HOXA10 and HOXA11 in a small number of individuals with sporadic uterine malformations.45 Other gene variants have been associated with Müllerian abnormalities,45 but to date, each has been found only in a small number of individuals.
abnormal uterine and/or stromal development, and normal endometrial Hoxa10 expression appears to be critical for implantation in adult mice.44 The possibility that some women with REPL and uterine malformations may be found to have altered gene expression in uterine tissues is intriguing, and variants of uncertain significance have been found in HOXA10 and HOXA11 in a small number of individuals with sporadic uterine malformations.45 Other gene variants have been associated with Müllerian abnormalities,45 but to date, each has been found only in a small number of individuals.
 Figure 1.1 Antiphospholipid syndrome. |
Whether acquired uterine abnormalities, such as leiomyomata, intrauterine adhesions, or endometrial polyps, are associated with REPL is not well established. One expert review concluded that multiple and intramural fibroids were associated with an increased proportion of pregnancies ending in miscarriage,46 but the relative risk was less than 2. A prospective cohort of over 5000 women with ultrasound assessment fibroids found no association of fibroids with pregnancy loss before 20 weeks.47 A systematic review of prospective studies concluded that nearly 20% of women suffering miscarriage have intrauterine adhesions, although these are mild in most cases.48 Moreover, it was found that women with recurrent miscarriages were more likely to have adhesions.48
Antiphospholipid syndrome (APS) is a widely accepted cause of REPL, with reports of from 5% to 15% of women affected by REPL testing positive for antiphospholipid (aPL) antibodies compared to 2% to 5% of women without miscarriages.16 International consensus criteria49 recognize three clinically relevant aPLs: lupus anticoagulant (LAC), anticardiolipin (aCL), and anti-β2-glycoprotein 1 (aβ2GP1) antibodies. Some experts also test for immunoglobulin (Ig) G and IgM antibodies to phosphatidylserine. APS is discussed in detail in Chapter 40, but a brief overview is warranted here.
The predominant pathogenic mechanism by which aPL antibodies may cause pregnancy loss has been reviewed.50 Pathogenic aPL antibodies recognize β2GP1, a glycoprotein constitutively expressed on the cell surface of trophoblast cells, as well as on many other cells, including maternal decidual endothelial cells. In extravillous trophoblasts, aPL antibodies promote pro-inflammatory, antimigratory, and antiangiogenic effects. aPL antibodies also displace annexin V, an inhibitor of coagulation, from the surface of trophoblastic cells.51 aPL antibody-induced immune activation, including complement activation, at the maternal-fetal interface results in pregnancy loss in animal models.52,53 Hypocomplementemia and increased complement activation products have been reported in women with APS and in association with adverse pregnancy outcomes, including miscarriage.54,55
The association of aPL antibodies with REPL is not without controversy.56 Overall, the published studies are highly heterogeneous, with many flawed by the inclusion of subjects with either poorly characterized pregnancy losses, especially regarding gestational age of loss, or the admixture of subjects with pre-embryonic, embryonic, and fetal deaths. Many studies also used nonstandard aPL antibody tests and/or “positive” results that do not meet international criteria definitions of positive. Some studies did not perform repeat testing to confirm positive aPL antibodies in accord with expert guidelines. Over the course of nearly a decade, two experienced groups of investigators have found fewer than 25 women with REPL as an isolated chief complaint (ie, without thrombosis, systemic lupus erythematosus, or fetal death), and with repeatedly positive aPL antibody titers, meeting international criteria.57,58
Endocrine Abnormalities
Screening for endocrinopathies is common practice in otherwise asymptomatic, that is, without overt disease, women with REPL. A detailed discussion of maternal endocrine disorders is presented in Chapter 31; discussion of diabetes in pregnancy is the topic of Chapter 30. A brief overview is provided here.
Thyroid Disorders
Retrospective studies suggest that recurrent pregnancy loss may be associated with overt hypothyroidism.59 A link between REPL and subclinical or mild thyroid disease is debated because of conflicting findings among available studies.60,61,62
Thyroid autoantibodies may be associated with REPL, and both anti-thyroid peroxidase antibodies (TPOAbs) and antithyroglobulin antibodies (TGAbs) have been implicated, although the evidence is stronger for TPOAbs. A meta-analysis found an increased risk of miscarriage in women with REPL and TPOAbs, even if the mother was euthyroid.63 However, a 2019 randomized trial of women with TPOAbs antibodies used very early urine pregnancy test screening and found that, of
the women who became pregnant, the pregnancy loss rate prior to 24 weeks was 30%, a figure that may not be remarkably different than the rate of pregnancy loss in the general obstetric population if pregnancy is identified at 3 to 4 weeks’ gestation.64
the women who became pregnant, the pregnancy loss rate prior to 24 weeks was 30%, a figure that may not be remarkably different than the rate of pregnancy loss in the general obstetric population if pregnancy is identified at 3 to 4 weeks’ gestation.64
Diabetes
Poorly controlled overt diabetes is associated with miscarriage at both high and low extremes of glycemic control.65 However, the relationship between overt glucose intolerance and REPL is poorly defined; the same is true for mild glucose intolerance or prediabetes. One case-controlled study found that serum fructosamine levels, an indication of average blood glucose over 1 to 3 weeks, were higher in women with REPL even after adjusting for BMI.66 Likewise, some studies showed an association between REPL and insulin resistance.67,68 Given the complex relationship between insulin resistance, obesity, and polycystic ovary syndrome (PCOS), the latter two are also thought to be associated with miscarriage.24
Polycystic Ovary Syndrome
PCOS is a common endocrine disease in women that is diagnosed with increasing frequency. The condition is likely a heterogeneous disorder associated with features that may be accompanied by other medical conditions. The diagnosis is criteria-based, and patients may be diagnosed via used different criteria. PCOS has been showed to have an association with REPL.69 However, the association of PCOS with REPL is complicated by the tendency of PCOS to be associated with other conditions (ie, increased BMI, insulin resistance, hyperandrogenism, and poor endometrial receptivity) that might contribute to increased risk of miscarriage.70
Luteal Phase Deficiency
Historically, luteal phase deficiency (LPD) has been defined as a condition in which endogenous progesterone production is insufficient to support the secretory endometrium and foster normal implantation. However, whether LPD exists as an independent entity affecting consecutive menstrual cycles has been questioned,71 and there is no consensus on the best method to make a diagnosis. Basal body temperature assessment, urinary luteinizing hormone (LH) detection kits, luteal progesterone levels, and endometrial biopsy interpretation are poorly reproducible, physiologically irrelevant, or clinical impractical.
Other Possible Etiologies
Inherited Thrombophilias
Thrombophilias are discussed in Chapter 2, but a brief overview is warranted here. Factor V Leiden (FVL) is the best-studied inherited thrombophilia with regard to REPL, but findings are inconsistent.75 Meta-analyses of retrospective data sets suggest an association of FVL with REPL.76,77 Three prospective observational studies of women with REPL and FVL showed a higher subsequent pregnancy loss rate in carriers compared to noncarriers,78,79,80 but the numbers of women with FVL were small in each study, and ORs were insignificant in two of the studies. In contrast, a large prospective study and two recent case-control studies did not find any association between FVL and REPL.81,82,83 Moreover, another study found that FLV was linked to a lower rate of EPL.84
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