The loss of a desired pregnancy, while sad, is not an uncommon event. It is well established that 15% of recognized pregnancies are lost (1), usually during the first 13 weeks of pregnancy (2), with the incidence of early pregnancy loss increasing with maternal age and a history of prior pregnancy loss. An additional 22% of conceptions are lost between implantation and the clini-cal recognition of pregnancy (preclinical losses), bringing the total rate of early pregnancy loss to nearly 40% of conceptions (3). The vast majority of fetal loss (4) occurs during the first trimester of pregnancy, with the loss rate dropping dramatically after 12 weeks’ gestation. The incidence of these early losses is directly correlated with the age of the mother, as the incidence of pregnancy loss increases threefold over the mean in women who are between 34 and 39 years of age, and sixfold in women over 40 years of age. As early as 1984, Hassold and Chiu (5) demonstrated that the pattern of age-related fetal loss closely mirrors the increased incidence of aneuploidy associated with advanced maternal age, suggesting a relation between these two phenomena. Yet, the obstetri-cal literature is replete with investigations of a variety of other causes of pregnancy loss, with little consensus on the factors responsible for the limited viability of human conceptions, and many reviews reiterating that in 50% of couples experiencing pregnancy loss, the causative factor cannot be determined. This chapter will review the data on the etiology of pregnancy loss, focusing on embryonic and fetal chromosome abnormalities and other established genetic causes that are usually associ-ated with fetal loss early in gestation, and discuss other
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factors that contribute to later pregnancy loss, as well as recurrent loss.
34.2 DEFINITION OF TERMS
Pregnancy loss can be defined as the unplanned, spontaneous loss of a pregnancy before the fetus is capable of extra uterine survival. In the United States, the term spontaneous abortion or miscarriage is applied to a pregnancy lost prior to 20 weeks’ gestation, after which time the loss is defined as either an intrauterine fetal death or stillbirth. Preclinical abortion (before 6 menstrual weeks’ gestation) occurs when the conceptus fails to implant or aborts shortly after implantation. The term missed abortion is used when the fetus has died but is retained in the uterus, often for several weeks. A pregnancy is classified as an inevitable abortion when uterine contractions cause dilation of the cervix, leading to either a complete abortion (all products of conception (POC) are expelled and the cervix subsequently closes) or an incomplete abortion (only a portion of the POC are passed through the cervix). Recurrent abortion has typi-cally been defined as two to three or more losses. Recur-rent fetal loss is less common, involving only 1–2% of couples, and recurrent fetal loss at or beyond 14 weeks of gestation is a very rare event.
The majority of spontaneous abortions occur in pregnancies with incomplete fetal development (6). However, abnormal development does not always end in spontaneous abortion, as is evident from the 3–4% population incidence of sporadic congenital anomalies in the newborn population.
2 CHAPTER 34 Fetal Loss
34.3 EARLY PREGNANCY LOSS
34.3.1 Cytogenetic Abnormalities in Human Conception
It has been known since the mid-1960s that chromosome abnormalities are found by cytogenetic evaluation of cul-tured tissue from spontaneous abortions in at least 60% of first-trimester losses. More recent data suggests that as high as 80% of first-trimester losses are the result of an unbalanced karyotype in the fetus, making chromosome anomalies the single most common reason for the loss of a pregnancy during the first trimester. An early epide-miologic study (7) on 1500 spontaneous abortion sam-ples collected from 1966 to 1972 reported that 61.5% of pregnancy losses in which the embryo was less than 12 weeks of age demonstrated a chromosome abnormality by culturing tissue collected at the time of the loss. His-torically, most laboratories culturing this type of “prod-ucts of conception” material find a significant excess of 46,XX karyotypes among the samples without a chro-mosome error, and this excess of 46,XX normal female results has been ascribed to nonviable fetal material with the growth of maternal tissue that was present in the sample collected. In such cases, it is the maternal, rather than the fetal karyotype that is being described, and this falsely inflates the number of “normal” fetal karyotypes reported. In addition, the early studies were done in the “pre-banding era,” when the techniques available would fail to recognize more subtle genomic abnormalities (such as deletions or duplications). Other complications limiting the evaluation of the true incidence of abnormal fetal genomes by doing tissue culture and routine chro-mosome analysis on abortus specimens include the rate of culture failure due to nonviable specimens (either due to missed abortions or samples with nonviable genetic alterations) and contaminated samples that cannot be grown and evaluated. Hence, the value of approximately 60% aneuploid fetuses reported by this and other early studies should be considered a minimum estimate of the incidence of chromosome abnormalities in miscarriages. Thus it is not surprising that a recent study, using semidi-rect analysis of chorionic villi (CV) from pregnancies that arrested in the first trimester (8) found that 80% of early pregnancy losses demonstrated a chromosome abnor-mality. As clinical evaluation of ongoing pregnancies have shown confined placental mosaicism, which is the presence of a chromosome abnormality in extraembry-onic tissue that is not present in the fetus, in only 1–2% of CV studies, this work of Morales et al. (8) suggests that upwards of 80% of early pregnancy losses actually are the result of a chromosome anomaly in the fetus.
The knowledge that 15% of recognized human preg-nancies are lost and that upwards of 80% of these are aneuploid, coupled with the frequency of unbalanced chromosome abnormalities in stillborns and live borns (5% and 0.4%, respectively), suggests that chromosome
abnormalities occur fairly frequently at conception in humans. Yet the “order of magnitude” decrease in the inci-dence of chromosome abnormalities from the first trimester of pregnancy, to the last trimester of pregnancy, and then again to birth, suggests that there is very strong selection against human fetuses with unbalanced chromosome com-pliments. A variety of methodologies, designed to improve preimplantation genetic diagnosis of embryos fertilized in vitro, have provided information addressing the incidence of abnormal karyotypes close to the time of conception. It is important to remember when evaluating these studies that they are complicated by the use of embryos created in vitro and the very manipulation of gametes and embryos in an artificial setting may affect genomic stability (9). In addition, besides discrepancies between the techniques themselves, the populations from which the embryos were obtained are not always equivalent, with varying ages and pregnancy histories, which as shown later, will influence the incidence of chromosome abnormalities. But these studies provide previously unrecognized information about the incidence and complexity of embryonic chromo-some abnormalities, and show an unanticipated very high frequency of chromosomal abnormalities in preimplanta-tion embryos, which may be correlated with the high inci-dence of early loss in both in vivo and in vitro embryos.
Fluorescence in situ hybridization (FISH) analysis of fertilized oocytes, early embryos and individual cells from such embryos obtained during the in vitro fertilization (IVF) process has provided new insights into the com-plexity of human reproduction. This approach uses dif-ferentially colored fluorescent probes, directed to single regions, often the centromere, of a chromosome, to assess the chromosome content of interphase cells. While this technique can be applied to single cells, or nonviable sam-ples, it is limited by the number of chromosome-specific probes that can be evaluated in a single study and thus cannot provide a complete chromosome analysis. These studies, depending on the probe set used, have confirmed a high level of aneuploidy (30–83%) in early embryos (10–15). In addition, these studies have revealed the pres-ence of both autosomal monosomy and nullosomy (10), which are virtually never observed in live borns or cell culture of miscarriage samples, but may contribute to the incidence of preclinical pregnancy loss. As seen in both prenatal diagnosis and newborn surveys, these studies revealed that the incidence of fetal aneuploidy is highly correlated with advancing maternal age (11), so that the incidence of aneuploid embryos observed is directly pro-portional to the mean maternal age in the group being studied. FISH done on multiple cells from early embryos also has shown a high rate of embryonic mosaicism, with up to 83% of 4-day embryos showing more that one cell population (12). The same study demonstrated that this mosaicism, which by definition is a postfertil-ization event, declines with further development of the embryo, possibly because of the death of abnormal cells, or an aneuploid rescue mechanism, so that only 42% of
CHAPTER 34 Fetal Loss 3
8-day embryos showed multiple cell lines. An even more unexpected observation was the presence in several multi-cell FISH studies of “chaotic embryos” showing extreme mosaicism with different chromosome abnormalities in almost every cell evaluated from the same embryo (12). All the aberrations detected by FISH contribute to the lack of viability of IVF embryos and, if also present in vivo, could explain the lower fertility rates seen in humans when compared to other mammals (10).
Molecular karyotyping by comparative genomic hybridization (CGH) has furthered the ability to assess the frequency and origin of chromosome abnormalities in both oocytes and embryos at various stages of devel-opment. This technology permits the assessment of both whole chromosome as well as segmental aneuploidy. However, the need to amplify the DNA from a single cell prior to array comparative genomic hybridization (aCGH) may introduce artifacts. Array-based CGH on human oocytes has demonstrated aneuploidy in 3–65%, depending on the study, age of the mother, and level of maturity (13). CGH following degenerate oligonucle-otide primed polymerase chain reaction (DOP-PCR) amplification of the DNA from single blastomeres of 12 human cleavage embryos (12) revealed only 3 to be nor-mal (25%), with 3 (25%) having evidence of meiotically derived aneuploidy (all cells with the same abnormality), and the other 50% showing mosaicism, a postfertiliza-tion event. Similarly, Wells and Delhanty (18) reported 75% of 3-day embryos to have chromosome abnor-malities with a high percentage of chromosomal mosa-icism. Both these early studies reported some “chaotic embryos” in which different chromosome abnormalities were observed in different cells from the same embryo. Using aCGH, Vanneste et al. (19) showed that while only 12.5% of fertilized human oocytes were chromo-somally unbalanced, 83% of 3-day embryos showed whole-chromosome aneuploidy. Only 3 of 19 (15.8%) of these embryos showed consistent abnormalities in all blastocysts, compatible with a meiotic origin of the abnormality, while the rest were mosaic. Healthy, cleav-age-stage embryos obtained by IVF (for evaluation of X-linked disorders, BRCA2 mutations, or familial micro-deletion syndromes, from woman less than 35 years of age, whose partners had a normal semen analysis, and without parental chromosome rearrangements) showed mosaicism in 91% of embryos. Whole-chromosome aneuploidy was observed in 83%, terminal segmental aneuploidy (deletions, duplications or amplifications) in 70% and uniparental disomy (UPD) in 9% (20). A comprehensive series of aCGH studies on 1290 human embryos from women aged 29–50 years (10) demon-strated that 58% of these blastocysts contained chro-mosome abnormalities. Subsequent single nucleotide polymorphism (SNP) analysis of these embryos revealed that only 43% of these abnormalities (representing 25% of all blastocysts) were due to meiotic errors. Overall, the range of genetic imbalance detected in embryos
by aCGH varies significantly from 12.5% to 83% (15,16,18,19,21,22), possibly a reflection of differences in the maternal populations from whom the embryos were obtained. Analysis of multiple single cells from a single embryo demonstrates a high level of postfertiliza-tion instability leading to both mosaicism and the chaotic embryos reported by FISH. Of note, in a majority of cases, embryos with mitotically derived errors (mosaic or chaotic embryos) were less likely to be viable than those with meiotic errors suggesting that many of the mitotic, postfertilization chromosome errors may contribute to infertility and preclinical loss, while the meiotic errors may be more commonly associated with the loss of rec-ognized pregnancies. In addition, aCGH has found more subtle chromosome imbalances in 2 of 11 fetuses (18%) reported to have a normal banded karyotype (21), indi-cating that even pregnancies reported to be normal and balanced by routine cytogenetics may harbor subtle seg-mental aneuploidies that contribute to their nonviability.
SNP arrays have been used to evaluate early embryos, and the limited reports using this methodology do not always support the high abnormality rates identified by FISH. A group specifically addressing this question by evaluating the same embryos with both FISH and SNP microarrays (22,23) reported significant discrepancies. In one study on 13 cleavage-stage embryos, nine-probe FISH demonstrated mosaic aneuploidy in 77%, while only 38.5% were abnormal on microarray analysis. In another study, the same group found consistency between FISH and microarray results in less than 50% of samples, with most of the discrepancies being in embryos reported to show monosomy or complex aneuploidy. Another group (24), using a different genome-wide genotyping SNP microarray and software that makes use of paren-tal genotypes to minimize error-prone single-cell micro-array data, found aneuploidy rates in early embryos of 20–70% depending on the age of the women from whom the embryos were obtained. Additional use of this approach may also be of value in determining the impact of UPD on pregnancy loss, which to date, has been reported to be infrequent (25).
34.3.2 Pattern of Chromosome Abnormalities Seen in Aborted Pregnancies
The vast majority of chromosomal abnormalities observed in aborted fetuses evaluated by G-banding are numerical, including autosomal trisomies, polyploidy, sex chromosome monosomy and double trisomies (26). A 2009 study, combining G-banding with MLPA and aCGH (27) on 115 first-trimester miscarriages, found 69 (60%) to be chromosomally abnormal. Of these, 69% had autosomal trisomy (including 2% with double tri-somies), 12% were polyploid (primarily triploidy), and 10% had sex chromosome monosomy (45,X), with only 1% showing structural abnormalities and the rest
4 CHAPTER 34 Fetal Loss
showing errors not involving entire chromosomes, such as duplications or deletions. Similar results were reported by combining karyotype analysis with reflex FISH (28), which observed 61% trisomy, 15% polyploidy (primar-ily triploidy), 14% sex chromosome monosomy and 7% structural abnormalities. It is not surprising that the most common abnormalities seen are autosomal triso-mies, as it was recognized as early as 1984 by Hassold and Chiu (5) that the risk of both pregnancy loss and the incidence trisomy as the result of maternal nondisjunc-tion increase with maternal age, and thus are likely to occur concurrently. Our own data (unpublished) shows the most frequent chromosome abnormalities in presum-ably sporadic fetal losses to be triploidy, sex chromo-some monosomy, and trisomies (21, 22, 15, 18, 13 and 16 in descending order (Figure 34-1)). A slightly different pattern was observed among losses from women with a history of pregnancy loss, with the most prevalent abnor-malities being triploidy, and trisomies 22, 16, 15 and 21. Interestingly, the pattern associated with sporadic loss is similar to that due to meiotic errors (9), while the pattern seen in the women with recurrent loss has been associated with mitotic errors seen in mosaic IVF embryos. The relative paucity of sex chromosome mono-somy among the recurrent losses might be related to the
slightly advanced age (37.3 vs 36.2 years) in this group, as sex chromosome monosomy is most often due to non-disjunction in males, and thus would not necessarily be related to maternal age. Double trisomies, which, except in very rare instances involving the presence of an extra sex chromosome, are not viable, are not uncommon in abortus samples, representing about 1–2% of these cases (29). They are almost always a result of maternal nondisjunction (30) and are also associated with older maternal age. It should be noted that while studies on preimplantation embryos (see earlier) often report auto-somal monosomy, peaking at about the eight-cell stage, such karyotypes are inviable, and autosomal monosomy has not been reported in abortus specimens.
34.3.3 Association of Advanced Maternal Age and Chromosome Abnormalities in Miscarriage
It is well established that increasing maternal age is the most important etiological factor associated with trisomy in humans. The National Down Syndrome Project (31) showed a significant association between advanced mater-nal age and trisomy 21 due to both meiosis I and meiosis II errors. This age-related increase in nondisjunction may be
FIGURE 34-1 Relative frequency of chromosome abnormalities observed in cytogenetically abnormal POCs from women with a reported history of recurrent pregnancy loss compared to those with reported sporadic pregnancy loss. Mean maternal age was 37.3 years in the recur-rent group and 36.2 years in the sporadic group. Number of chromosomes involved presented across the X axis with 23 = double trisomy, 24 = monosomy X, 25 = triploidy, 26 = tetraploidy. The abnormalities that are considered viable (trisomy 13, 18 and 21 and monosomy X) are all more frequent in the group with sporadic losses, with trisomies 15, 16 and 22 being more prevalent among those with recurrent loss.
CHAPTER 34 Fetal Loss 5
due to alterations in the cohesin complex (32,33) or differ-ences in the patterns of recombination (34) during meio-sis. Since the incidence of miscarriage also increases with maternal age, going from 10% in women 20–24 years of age to over 90% in women over 45 years of age (35), most pregnancy losses, especially those in older women, are associated with errors due to maternal nondisjunction. Boue and colleagues (36) reported that the mean mater-nal age of woman whose abortuses demonstrated a chro-mosome anomaly was increased compared to those with normal fetal results. This is consistent with the increased incidence of autosomal trisomy with advancing mater-nal age. Hassold and Chui (5) confirm this association, reporting that the rate of trisomies seen in spontaneous abortions is 20% in women under 25 years, 33% for those 30–35 years of age, and at least 67% in women who are 40 or older. Similarly, Fragouli and Wells (10) found that older women had a tendency to generate more chromosomally abnormal blastocysts, with an aneuploidy range of 46.5% in women 34 years of age or younger and 60.6% in women over age 35. In one set of SNP micro-array studies sited earlier (22,23), the incidence of fetal aneuploidy increased from 19.6% when the mean mater-nal age was 31 (range 22–37 years) to 76.9% with a mean maternal age of 38.8 (range 32–44 years). Thus, it can be inferred that most pregnancy losses result from a fetal chromosome abnormality, and that this is particularly true in older women, who comprise a disproportionate number of those experiencing pregnancy loss.
34.3.4 Relative Incidence of Chromosome Abnormalities in Sporadic vs Recurrent Pregnancy Loss
Women who experience pregnancy loss usually take longer to achieve their desired family size, and so are often attempting pregnancy at older ages. Thus, the age-related incidence of nondisjunction and associated fetal chromosome abnormalities (see earlier) could be con-tributing to their unsuccessful pregnancy history. In a case-control study (37) women having experienced two consecutive miscarriages were found to be older than controls, with 42.6% being older than 35 years of age, while in the control group the percentage of women over 35 years was only 13.9. In addition, the risk of repeated miscarriage was threefold higher in women over 35 as compared to those 25–29 years of age. Rubio et al. (38) performed PGD on 71 couples with a history of recur-rent miscarriage and a age-matched control group of 28 couples undergoing PGD because of the risk of sex-linked diseases (without other infertility problems) and observed that the couples with recurrent miscarriage produced chromosomally abnormal embryos at a higher rate than those not having this reproductive problem. Marquand et al. (39) evaluated first-trimester losses in 180 women who were over 35 years of age. Of these, 24% had expe-rienced at least three prior losses. In this recurrent loss
group, the incidence of aneuploidy was 78%, which was not statistically different from the 70% aneuploidy rate in the sporadic group. Both groups had similar mean mater-nal ages. Bianco et al. (40) observed that, the more preg-nancy losses a woman had experienced, the greater the likelihood that she would be found to have a fetus with a chromosome abnormality at prenatal diagnosis. In their evaluation of nearly 47,000 women undergoing prena-tal diagnosis, the incidence of an abnormal fetal karyo-type increased from 1.39% in those with no history of pregnancy loss to 2.18% in those who had three or more losses. Our own data (unpublished) on POC shows the incidence of at least one chromosomally abnormal sam-ple from women where we received at least two POCs was 73.9% compared to the overall abnormality rate of 49.5%. These observations would tend to refute the con-cept that recurrent pregnancy loss is primarily due to fac-tors other than chromosome abnormalities in the fetus.
34.3.5 Parental Chromosome Abnormalities
Although fetal chromosome abnormalities are extremely common in miscarriage samples, most of the abnormalities observed are numerical and de novo, and do not necessitate parental chromosome analysis. How-ever, there are situations in which parental chromosome analysis is indicated, as parental balanced chromosome rearrangements can lead to abnormalities in meiosis and the generation of unbalanced gametes.34.3.5.1 Structural Rearrangements. Couples experi-encing two to three pregnancy losses are often referred for chromosome analysis, as a vast literature (2,41–46) sug-gests that in about 5% of these couples, one of the part-ners will have a balanced chromosome rearrangement (either a translocation or an inversion). Mau-Holzman (47) in a study of the somatic karyotype of infertile men and women found chromosome rearrangements in 4% of men with azoospermia, 24% of men with oligosper-mia, and 20% of women who were candidates for ISCI, confirming the principle that meiosis in individuals with balanced chromosome rearrangements often generates unbalanced gametes leading to nonviable conceptions associated with either infertility or pregnancy loss. The incidence of parental chromosome abnormalities is lower than this in couples achieving, but subsequently losing pregnancies (48–53), being in the range of 2.7–7.6% (for comparison, the incidence of balanced chromosome rearrangements detected in 269,371 prenatal diagnosis studies was only 0.09% (54) and only 0.2% in a popula-tion of phenotypically normal, fertile adult males being tested as sperm donors (52)). Couples with one partner who has a balanced chromosome rearrangement tend to have a very poor pregnancy history, because of the pro-duction of genetically unbalanced gametes and fetuses. Sugiura-Ogasawara et al. (42) evaluated couples in which one partner was known to carry a translocation
6 CHAPTER 34 Fetal Loss
and observed a pregnancy loss rate of 61% if the trans-location was carried by a male and 72% if carried by a female. Thus, some clinicians recommend that these couples undergo IVF with PGD in the hopes of achieving a pregnancy with a balanced karyotype.34.3.5.2 Mosaicism. The empirical risk for recurrence of autosomal trisomy, after a couple has experienced one such pregnancy, is routinely quoted as 1%. Several older studies demonstrated that this 1% recurrence rate may be explained by the presence of parental mosaicism for an autosomal trisomy, including gonadal mosaicism, and that 1% of couples who give birth to a child with an autosomal trisomy demonstrate such mosaicism. Since fetal autosomal trisomy, even those trisomies that are considered viable, is often associated with pregnancy loss, parental mosaicism might contribute to the occur-rence of chromosomally abnormal pregnancy losses, especially in couples with recurrent losses. Although there are several isolated reports of the finding of paren-tal mosaicism in couples with a history of pregnancy loss (55–58), Kuo (56) reviewed karyotypes from 1010 couples with a history of recurrent spontaneous abortion (blood lymphocytes and skin fibroblasts) and found only two women (0.2% of couples) who demonstrated mosa-icism for chromosome 21. An earlier study, showing that the recurrence of the same chromosome abnormality in subsequent losses (60) did not occur more often than expected by chance, also concluded that the incidence of gonadal mosaicism was low in couples with recurrent
abortion. However, Warburton et al. (61) did find a higher recurrence risk for trisomy 21 mosaicism only among younger mothers with repeat losses, suggesting that in this population, gonadal mosaicism may explain some recurrent losses.
34.3.6 Other Causes of Pregnancy Loss
While the single most common reason for the loss of a recognized pregnancy during the first trimester is the presence of a genetically unbalanced fetal genotype asso-ciated with an abnormal karyotype, many other factors have also been investigated (Table 34-1). Some women, who experience pregnancy losses, may do so because of underlying maternal diseases, which may be amenable to treatment. Any disease that can potentially decrease uterine-placental blood flow profoundly may be impli-cated in causing a fetal demise. These could include maternal hypertension, systemic lupus erythematosus (SLE), insulin-dependent diabetes mellitus, sickle-cell disease, renal disease with hypertension, severe maternal trauma, and drug exposure. Women who were them-selves exposed to diethylstilbestrol in utero also show an increased incidence of spontaneous abortion, ectopic pregnancies and preterm births, presumably as a result of congenital tubal or uterine abnormalities induced by their exposure to the drug during embryogenesis (62). Unfortunately, many of the studies involving these potential causative factors have investigated the couples
TABLE 34-1 Evaluation and Management of Recurrent Early Pregnancy Loss
Thrombophilia 8–12 Factor V Leiden mutation Heparin/enoxaparinProthrombin gene mutationFasting homocysteine level Folic acidAntithrombin III activityProtein C activityProtein S activity
Environmental 5 Review exposure to alcohol, tobacco and caffeine Eliminate exposureReview exposure to environmental chemicals and toxins
experiencing losses, without appropriate control popu-lations or taking into consideration the chromosomal status of the fetus. Thus, some of the possible causes of pregnancy loss addressed in the prior version of this text (e.g. HLA similarities between parents and skewing of X-inactivation) have since been discredited (63–66), and will not be addressed here. However, in the minority of couples experiencing the loss of chromosomally normal fetuses, these factors can be explored, as potential rem-edies exist for some.
34.3.7 Other Genetic Factors
34.3.7.1 Single Gene Disorders. A few single gene disorders have been associated with both early and late pregnancy loss including stillbirth. These include hemoglobinopathies, inborn errors of metabolism and inherited thrombophilias. Most of these disorders are inherited in an autosomal recessive fashion. Thus, consanguinity increases the risk for these disorders in that the likelihood that both parents carry the same autosomal recessive mutation is increased, as a result of “identity by descent.” Alpha thalassemia major is an example of a single gene disorder that can cause pregnancy loss (67,68). Alpha thalassemia causes pregnancy loss when both parents carry complete deletions (null alleles) that are in the cis configuration. This results in deletion of both α-thalassemia genes on the same chromosome. If the fetus inherits the deleted chromosome from both parents, it will be deleted of all four α-globin genes, resulting in hemoglobin Barts and hydrops fetalis leading to fetal death in the second and third trimesters. Individuals of Southeast Asian ancestry are at greater risk to carry the cis configuration and to have affected offspring. However, the majority of autosomal recessive disorders are not associated with increased risk for early pregnancy loss.
Most genetics textbooks include a discussion of X-linked dominant disorders, the majority of which are lethal in males, including pedigrees depicting multiple losses of male pregnancies. However, the list of disorders in this group is small (Table 34-2) and the incidence of carriers is very low, so that this is a very infrequent cause of pregnancy loss. For the rare families in this category, PGD may help to achieve a desired family size.
There are limited data to suggest that other familial mutations might increase the risk of pregnancy loss in certain families. Transmission rate distortion has been reported for spinal muscular atrophy (69,70), which could be explained by the early loss of some fetuses homozy-gous for the mutant allele. A study investigating the inci-dence of variants of BRCA2 in newborns (71) found a deviation from the Hardy–Weinberg equilibrium, with reduced fitness for homozygotes with variant alleles sug-gesting reduced prenatal viability for these genotypes. For individual families, heterozygosity for a common allele in the parents may contribute to recurrent loss, as has been reported in some consanguineous populations (72).
CHAPTER 34 Fetal Loss 7
34.3.7.2 Thrombophilias. The thrombophilias are a group of disorders in which there is a propensity to develop venous or arterial thrombosis. Both inherited and acquired thrombophilias and the associated throm-bosis of placental vessels have been proposed to influence pregnancy loss (73–75). Mutations in the genes for both factor V and prothrombin have also been associated with unexplained late fetal loss and other thrombosis-related pregnancy complications (76,77). Factor V Leiden (FVL) mutations and the associated resistance to activated pro-tein C are reported to be more prevalent in woman with a history of pregnancy loss in several studies (76,79–86), with an incidence of 7–44% in those with losses as com-pared to 1.6–6% in controls. Studies on mice, made deficient for factor V through gene targeting, show that half the embryos die during the first half of gestation, probably as a result of abnormalities in yolk-sac vascu-lature (87). Earlier reports suggested that FVL deficiency is associated with preeclampsia, abruptio placentae, fetal growth restriction, late pregnancy loss and stillbirth. Yet, a number of large collaborative studies have not confirmed this association (88–90). An additional hered-itary thrombophilic tendency implicated in recurrent pregnancy loss is hyperhomocysteinemia, which has also been associated with other thrombotic morbidities, such as adult myocardial infarction (91–93). Some reports have shown an association between a homozygous C->T polymorphism at nucleotide 677 in the gene coding for methylenetetrahydrofolate reductase (MTHFR), which leads to a thermolabile variant of the enzyme and low levels of serum folate, hyperhomocysteinemia and early pregnancy loss (91,94,95). The combination of serum folate deficiency and hyperhomocysteinemia has been reported to result in defective chorionic villus vascular-ization (93) and would be amenable to treatment with relatively high doses of folic acid (5 mg/day) along with pyridoxine supplementation (91). Two meta-analyses
TABLE 34-2 X-Linked Dominant, Male Lethal Disorders Are Rare
Disorder/MIM Incidence
Aicardi 304050 1:93,000–1:167,000Chondrodysplasia punctata 302960 1–9/1,000,000Congenital hemidysplasia with ichthyosiform
erythroderma and limb defects (CHILD) 308050
<1/1,000,000
Goltz syndrome (focal dermal hypoplasia) 305600
<1/1,000,00095% new mutations
Incontinentia pigmenti 308300 1–9/1,000,000Microphthalmia with linear skin defects
309801<1/1,000,000
Oculo–facio–cardio–dental 300166 <1/1,000,000Oral–facial–digital type I 311200 1:250,000–1:50,000Rett 312750 1:8500Terminal osseous dysplasia 300244 <1/1,000,000Wildervanck syndrome 314600 ?
8 CHAPTER 34 Fetal Loss
and related studies of thrombophilic disorders and fetal loss showed an association between FVL, activated pro-tein C resistance or the prothrombin G20210A (PGM) mutation and recurrent early fetal loss, but demonstrated no association between the MTHFR mutation and fetal loss (96–98). A combination of heparin or enoxaparin and low-dose aspirin is recommended for treatment of pregnant women with FVL and prothrombin gene muta-tions (98). This is the current protocol followed at our center.34.3.7.3 Autoimmune Disorders. The presence of autoimmune antibodies, with or without other stigmata of autoimmune disease, has been described as a risk fac-tor for recurrent pregnancy loss. The role of autoimmune antibodies as the cause or result of the pregnancy loss has been influenced by studies of the effect of thrombophilia on pregnancy loss rates (Table 34-3). During pregnancy and the postpartum period, SLE, with a prevalence of
TABLE 34-3 Factors that Contribute to Vascular Problems in the Placenta
1–1.6% in the female population (99,100), can be asso-ciated with a series of remissions and exacerbations with an increased risk of “flares” during pregnancy (101). If the disease is in remission at the time of conception, the fetal survival rate is quite good, about 85% (102), but still below that seen in unaffected women. However, if SLE is active during the pregnancy, particularly if a lupus flare occurs in the first trimester, the fetal survival rate decreases to 50–75% because of complications of placental thrombosis and hypertension (103) associated with lupus flares. Similarly, several connective tissue diseases that produce circulating antibodies, such as Ro (SSA), can lead in utero to complete heart block (104) and pregnancy loss.34.3.7.4 Antiphospholipid Syndrome. The antiphos-pholipid syndrome involves the presence of a spectrum of antibodies directed against cellular phospholipid components. This syndrome has been associated with arterial and venous thrombosis, recurrent pregnancy loss, and immune thrombocytopenia in the absence of rheumatologic disease. The antiphospholipid syndrome is defined on the basis of clinical and laboratory criteria. The criteria proposed by Laskin et al. (105) are shown in Figure 34-2.
The obstetrical literature reports that certain antiphospholipid antibodies, particularly lupus antico-agulant and anticardiolipin IgG and IgM, are associated with recurrent early pregnancy loss. Elevated levels of both antiphospholipid antibodies (lupus anticoagulant) and anticardiolipin IgG and IgM have been reported in women with a history of pregnancy loss (106). Both these classes of antibodies lead to a higher incidence of thrombotic events (lupus anticoagulant interferes with the conversion of prothrombin to thrombin), causing placental thrombosis and infarction (107). Thus, while the presence of these antibodies has been associated with
Clinical Criteria
Vascular thrombosis
Adverse pregnancy outcome
At least one unexplained pregnancy loss after 10 weeks GA
Three or more unexplained, consecutive pregnancy losses before 10 weeks
GA
One or more preterm births of a normal neonate at or before 34 weeks GA
because of preeclampsia, eclampsia or placental insufficiency
Laboratory Criteria
Moderate or high titer IgG or IgM anticardiolipin antibody measured on two or more
occasions at least 6 weeks apart
Circulating anticoagulant measured on two or more occasions at least 6 weeks apartFIGURE 34-2 Criteria for classification of antiphospholipid syndrome.
pregnancy loss in any trimester, most of the losses occur later in pregnancy (108). Antiphospholipid antibodies were detectable in 16% of patients with three or more pregnancy losses as compared with 7% of normal con-trols, and in only 3% of women who had never reported a pregnancy (109). Creagh et al. (110) reported the inci-dence of women with lupus anticoagulant or anticardio-lipin as 7/35 and 6/35, respectively, in a group with more than two losses, as compared to 1/31 and 0/31 in a group with two or fewer losses. However, low-positive IgG fractions of antiphospholipid antibodies or isolated IgM fractions do not establish a diagnosis of the antiphos-pholipid syndrome. Women with prior fetal losses and high levels of anticardiolipin IgG antibodies appear to be at the highest risk of fetal loss in subsequent pregnan-cies and may benefit the most from preventive therapies (111). An elevation of antinuclear antibodies occurred in the sera of a woman with previous pregnancy loss, even when the loss had been explained by other causes such as anatomic or luteal phase defects (LPD) (112). How-ever, antinuclear antibodies alone appear to be nonspe-cific markers in women with pregnancy loss, with other investigators demonstrating no difference in the pro-portion of positive antinuclear antibody tests between women with recurrent losses and appropriate controls (112). Takakuwa et al. (113) observed that the incidence of chromosomally abnormal abortuses was lower in woman with elevated anticardiolipin antibodies (20% as compared to 60% in controls), suggesting that some of their losses were not due to chromosome abnormali-ties, but associated with this autoimmune phenomenon. Whether some of these autoimmune antibodies are gen-erated in response to fetal demise in susceptible women rather than being the cause of the pregnancy loss has been cause for speculation. However, immunoglobulin isolated from women with elevated anticardiolipin levels can induce abortion in pregnant mice (114), suggesting that the antibodies themselves may be the underlying eti-ology of the loss. In addition, several studies have sug-gested the use of corticosteroids, heparin, aspirin, and immunoglobulin therapy in preventing pregnancy loss in women with antiphospholipid antibodies (108–118). Controlled trials have confirmed the efficacy of low doses of aspirin and/or heparin (119–121). Interestingly, the efficacy of heparin may be due to its inhibition of complement activation rather than its anticoagulant effects (122). Other antiphospholipid antibodies such as antiphosphatidylserine and β2-glycoprotein-1 may be associated with recurrent pregnancy loss. However, the evidence for this association is weak (123).34.3.7.5 Endocrine Disorders. A number of maternal endocrine disorders have been linked to pregnancy loss.
34.3.7.5.1 Diabetes Mellitus. In nonpregnant women of child-bearing age, the term type I diabetes is used to include all insulin-dependent diabetes, while type II diabetes implies non-insulin-dependent disease. In pregnancy, classification is based on whether or not
CHAPTER 34 Fetal Loss 9
a woman has had diabetes prior to pregnancy. Preges-tational diabetes is then subdivided into alphabetical classes depending on the age of onset, duration of the disease, or both and whether any diabetic vascular com-plications occurred. Gestational diabetics have diabetes only during pregnancy and are classified as A1 if con-trolled with diet only, and A2 if insulin is needed (124). Even prepregnancy obesity, possibly through its associa-tion with insulin resistance and the metabolic syndrome, has been associated with an increase in stillbirths and neonatal deaths (125). Poorly controlled diabetes mel-litus is known to cause miscarriage. Elevated glycosyl-ated hemoglobin levels associated with poor glycemic control in early pregnancy are associated with sponta-neous abortion. In contrast, the risk for pregnancy loss is not increased in women with well-controlled diabetes (126). Metabolic control of diabetes prior to conception and during the first trimester dramatically influences both the risk of spontaneous abortion and the incidence of major congenital anomalies (126,127). The perinatal mortality rate of about 3% in well-controlled diabetic women has been stable for over 30 years (128), with associated elevated risks for preeclampsia and preterm delivery. Poorly controlled diabetes is associated with an even higher perinatal death rate (129). Excluding lethal fetal anomalies, maternal complications of ketoacidosis, pregnancy induced hypertension (PIH), pyelonephri-tis, or neglect increase the perinatal mortality rate to as high as 17% (130). Preeclampsia was diagnosed in about 12.7% of diabetic women and preterm labor in 32% (125). Major congenital anomalies were increased threefold in diabetic pregnancies, but excellent prepreg-nancy control can markedly reduce the incidence of malformations (126,128). In a recent outcome survey of 273 women with type I diabetes, although the congeni-tal abnormality rate was twice that seen in the general population, the rate of miscarriage was 14.7%, which is within the background rate (125,131). Even elevated maternal weight, which may be associated with type II diabetes, has been implicated as a risk factor for preg-nancy loss (132). Early detection, excellent control, fetal surveillance, and blood pressure monitoring are key fac-tors in lowering the perinatal mortality rate associated with maternal diabetes.
34.3.7.5.2 Luteal Phase Defect. During the luteal phase of the menstrual cycle, the corpus luteum produces progesterone, which induces the secretory changes in the endometrium that are necessary for implantation and maintenance of pregnancy. Once pregnancy occurs, the corpus luteum continues to secrete progesterone until the placenta produces enough progesterone to maintain the pregnancy.
LPD is defined as a lag of more than two days in the histological development of the endometrium compared with the day of the menstrual cycle. This retardation in endometrial development in the peri-implantation period may be associated with recurrent miscarriage. However,
10 CHAPTER 34 Fetal Loss
many studies of this phenomenon have not included concurrent controls, and normal women can have endo-metrial histology suggestive of LPD in up to 50% of menstrual cycles, suggesting that the association between LPD and recurrent pregnancy loss remains speculative.
A midluteal phase serum progesterone of <10 ng/mL is considered to be diagnostic of an inadequate luteal phase. Uncontrolled studies suggested that treatment with progesterone improves pregnancy outcome in women with recurrent miscarriage. However, several meta-analyses of controlled trials revealed no statistically significant difference in miscarriage rate between proges-tins and placebo or no treatment (133). Well-designed randomized trials are needed to establish the efficacy of progesterone supplementation in the treatment of recur-rent early pregnancy loss.
34.3.7.5.3 Thyroid Disorders. Clinical hypothy-roidism and hyperthyroidism have both been associated with decreased fertility and increased pregnancy loss rates. In particular, untreated or inadequately treated hypothyroidism has been associated with an increased risk for spontaneous abortion (134). Subclinical thyroid dysfunction, however, has not been linked to pregnancy loss (134,135). Antithyroid antibodies are more frequent in women with recurrent pregnancy loss, although, if the patient is clinically euthyroid, the presence of antithy-roid antibodies does not appear to influence pregnancy outcome (136). In patients with clinical hypothyroidism, treatment with thyroxine, and subsequent restoration of normal thyroxine levels, reduces the risk for pregnancy loss.
34.3.7.5.4 Hyperprolactinemia. Hyperprolactinemia has also been suggested as a cause of miscarriage by affect-ing the hypothalamic–pituitary axis and causing inad-equate oocyte maturation and luteal phase deficiency. However, evidence from controlled studies to support this theory is lacking. In an observational study involving 54 hyperprolactinemic women who underwent 64 preg-nancies, Crosignani et al. (137) reported a miscarriage rate of 25%. In a series of 64 women with hyperpro-lactinemia who underwent 103 pregnancies (78 treated with bromocriptine and 25 untreated), Rossi et al. (138) reported an increased rate of ectopic pregnancy in the untreated group (24% vs 5%, p < 0.02) but no increase in rate of spontaneous abortion. However, in one study involving 64 women with hyperprolactinemia among 352 women with recurrent pregnancy loss, treatment of hyperprolactinemia with bromocriptine was associ-ated with a decrease in the rate of recurrent pregnancy loss (139).
34.3.7.5.5 Polycystic Ovarian Syndrome. Poly-cystic ovarian syndrome has also been investigated in women with recurrent spontaneous abortions (140). Over 40% of women with recurrent loss demonstrated features consistent with polycystic ovarian syndrome. However, as the successful pregnancy rate in these women was similar to that of normal controls, it is
unlikely that this disorder is related to pregnancy loss in ovulatory women.34.3.7.6 Nongenetic Factors. Pregnancy losses beyond the first or early second trimester have been associated with nongenetic factors such as maternal structural anomalies, infection or trauma.
34.3.7.6.1 Uterine Anomalies. Defects caused by abnormal Müllerian fusion are a recognized cause of pregnancy loss. The presence of an intrauterine septum has been associated with recurrent early pregnancy loss. However, other Müllerian anomalies such as bicornu-ate and unicornuate uterus have been associated with second-trimester losses or preterm delivery rather than first-trimester losses (141). Observational studies sug-gest that surgical resection of intrauterine septae is asso-ciated with improved pregnancy outcome. Lin et al. (141) reported a study involving 36 women who had complete uterine septae with double cervix and vagi-nas. Twenty-one women who underwent hysteroscopic metroplasty were compared with 15 women who had no treatment. The rate of spontaneous abortion prior to the study was similar in both groups. The spontaneous abor-tion rate in the subsequent pregnancy was 11.1% in the metroplasty group and 87% in the no treatment group (p = 0.03) (141). Women with uterine leiomyomata have been reported to be at increased risk for second-trimester spontaneous abortion (142,143). Submucous myomata can result in distortion of the uterine cavity and have been associated with recurrent pregnancy loss in observa-tional studies. A recent meta-analysis showed no signifi-cant benefit from hysteroscopic myomectomy in women with submucous myomas (relative risk (RR) = 1.6; 95% confidence interval (CI) = 0.7–3–3.6) (144). Endometrial polyps and intrauterine adhesions or synechiae (Asherman syndrome) secondary to uterine currettage, particularly in the presence of endometritis, have been associated with recurrent pregnancy loss in uncontrolled studies. Hysteroscopic polypectomy and lysis of adhesions has been reported to be associated with improvement of fer-tility in patients undergoing IVF (144,145). However, to date, there are no controlled studies demonstrating a reduction in recurrent early pregnancy loss rates with hysteroscopic polypectomy or lysis of adhesions. Struc-tural defects of the uterus have been reported in 15–30% of women who habitually abort as compared to 0.5–2% of normal controls (146), and sonohysterography of woman with at least two prior losses revealed intra-uterine abnormalities in 50% (147), suggesting a causal relationship. Surgical correction of uterine abnormalities may be a reasonable option if other causes of recurrent pregnancy loss have been excluded. It is reported that 82% of patients with histories of recurrent loss, who underwent surgical correction of a septate uterus, deliv-ered viable infants in their subsequent pregnancies (148). Cervical insufficiency (incompetent cervix) has been associated with preterm labor and pregnancy loss. Clas-sically, cervical insufficiency presents as painless dilation
without labor, resulting in bulging of the fetal mem-branes into the vagina. Subsequently, the membranes can rupture and cause expulsion of a previable fetus. This condition, when diagnosed, is amenable to treatment by cerclage. Historically, the necessity of this procedure has been controversial (149). A recent meta-analysis of five randomized trials found that composite perinatal mor-tality and morbidity were significantly reduced (15.6% vs 24.8%) in women with previous spontaneous pre-term birth and short cervix (<25-mm length by vaginal ultrasound) who were treated with cerclage (150). The recognition of a treatable anatomic abnormality often terminates the search for other causes of pregnancy loss.
34.3.7.6.2 Infectious Agents. Pregnancy-related infec-tions are uncommon, but have been reported to be a cause of fetal loss. Mumps and measles, when acquired during pregnancy, have been associated with increased rates of spontaneous abortion (151). Other maternal infections, such as cytomegalovirus (CMV), parvovirus B-19 and syphilis, can result in second- or third-trimester fetal death (152,153) because of the sequelae of overwhelm-ing fetal infection. A few other bacterial and protozoan microorganisms have been associated with spontaneous abortion including Mycoplasma hominis, Ureaplasma urealyticum, Brucella abortus, Salmonella typhi, Vibrio fetus, Chlamydia trachomatis, and Toxoplasma gondii. Transplacental infection has been reported with each of the above agents, making them a possible cause of mis-carriage. However, in a study of 818 women enrolled in the early first trimester, Simpson et al. (154) found no dif-ference in clinical infection among 112 women who had pregnancy losses compared with 702 women who had successful pregnancy outcomes. In addition, in a study of 54 chromosomally normal abortuses, PCR of CV showed no evidence of U. urealyticum, M. hominis, CMV or ade-novirus, while eight specimens revealed human papilloma virus and one specimen showed C. trachomatis (155).
Other infectious diseases, such as rubella and varicella (156,157), may produce a substantially increased risk of structural fetal abnormalities, or developmental abnor-malities, such as CMV, without intrinsically increasing risk of fetal loss (158).
34.3.7.6.3 Teratogens. Exposure to teratogenic agents during pregnancy is known to produce abnormalities of form or function, including fetal wastage. The patho-genetic mechanisms leading to fetal death may occur through disturbance of one or more developmental pro-cesses. These include hypoplasia or hyperplasia of devel-oping tissues, failure of cell differentiation, interaction or migration, or mechanical disruption of cells. Often, the end result of teratogenic action is an organ with too few cells. Subsequently, the organ system may fail to develop fully because of a lack of critical mass required for differentiation. Pregnancy loss due to teratogenetic agents is often difficult to prove conclusively, and many relatively safe agents have been incorrectly implicated from anecdotal experience. Gardella and Hill (159)
CHAPTER 34 Fetal Loss 11
reported that the only teratogens that are convincingly associated with pregnancy loss are ionizing radiation (the Hiroshima experience), organic solvents, alcohol, mercury and lead, with some additional data implicating cigarettes. However, the majority of known teratogens are not associated with an outcome as severe as fetal death. Table 34-4 lists agents that include pregnancy loss as part of their related effects. Certain classes of drugs, such as folic acid antagonists (aminopterin and metho-trexate) are well-documented abortofacients and have been specifically studied in terms of the timing and dose required for subsequent fetal wastage (160). Cancer during pregnancy is a rare occurrence, with an incidence of about 0.04% (161). The most common malignancies include those of the breast, cervix, thyroid, ovary, and lymphoma. Pregnancy outcome appears to be extremely good in women with hematological malignancies (162). Chemotherapy in the first trimester has been associated with an increased incidence of abortion and fetal abnor-malities (163). Antineoplastic agents in general raise serious concerns regarding the mutagenic, teratogenic, and abortifacient effects on the human embryo. How-ever, with the exception of aminopterin and methotrex-ate (160), individual agents have not been sufficiently studied to determine whether a clear risk for pregnancy loss exists.
34.3.7.6.4 Maternal Stress. Maternal psychological stress has been considered to be a risk factor for early pregnancy loss. However, scientific evidence to sup-port the association between stress and miscarriage is sparse. In a study comparing urinary cortisol levels dur-ing the first 3 weeks post conception between 9 women who carried to term and 13 women who miscarried, Nepomnaschy et al. (164) found higher mean cortisol levels in the women who miscarried (RR = 2.7 (95% CI = 1.2–6.2)). They concluded that increased levels of
TABLE 34-4 Teratogenic Agents Associated with Fetal Wastage in Human Pregnancy
cortisol serve as a stress marker for higher risk for preg-nancy loss. Several studies have reported that support-ive care in early pregnancy for women with a history of recurrent spontaneous abortion resulted in a reduction in risk for subsequent pregnancy loss (165,166). For women whose losses were not attributable to identifi-able pathology, Clifford et al. (166) reported a rate of successful outcome in the next pregnancy of 69%. This was compared with a successful pregnancy rate of 49% for the women who did not attend the clinic for early supportive care. In the subgroup of women with favor-able prognostic features (age less than 40; less than six prior losses), the success rate in the next pregnancy was 79%. Medical therapy and other interventions are often prescribed for women with recurrent losses even in the absence of underlying causes in an attempt to improve outcomes of subsequent pregnancies.
Based on the above findings, women without underly-ing pathology can be counseled that the outcome for the next pregnancy is likely to be favorable with supportive care alone.
34.3.7.6.5 Maternal Trauma. Trauma during preg-nancy is not an uncommon occurrence. Approximately 6–7% of pregnancies are affected by some degree of traumatic injury. These injuries are usually acciden-tal but may be a result of intentional violence (167). Trauma is one of the leading causes of maternal death, accounting for up to 46% of cases (168). Factors that predict fetal loss in the face of maternal trauma include the severity of injury, maternal acidosis, hypoxia, shock, severe head injury, direct uteroplacental injury, placen-tal abruption, coagulopathy and maternal death (169). Most studies reporting pregnancy loss rates following maternal trauma have involved perinatal losses in the late second and the third trimesters. There are very limited data regarding maternal trauma and risk for early preg-nancy loss. With respect to intentional trauma, Nelson et al. (170) reported the results of a nested case-control study involving 392 women who experienced spontane-ous abortion prior to 22 weeks and 807 controls who carried their pregnancies beyond 22 weeks. The authors were unable to demonstrate a relationship between any measure of physical violence and spontaneous abortion. Despite these findings, domestic violence is an important problem. More than 40% of women of reproductive age have experienced at least one episode of violence in their lifetime. As such, domestic violence is a very prevalent and alarming public health issue.
34.4 LATE PREGNANCY LOSS
Second- and third-trimester pregnancy loss, although much less common than first-trimester miscarriage, is still a very important event in a woman’s reproductive history. A number of retrospective studies have shown an association between prior second-trimester loss and
increased risk for spontaneous preterm birth and recur-rent second-trimester loss in subsequent pregnancies (171–173). In some studies, second-trimester losses are classified along with those that occur in the first trimester. However, it is important to recognize that the causes for loss in later pregnancy are often distinctly different from those observed in the first trimester. Factors associated with late pregnancy loss include fetal structural anoma-lies (including cytogenetic abnormalities), maternal ana-tomic abnormalities, abnormal first- or second-trimester serum screening results, infection, and inherited throm-bophilias. Late losses generally include those occurring after 14 weeks of gestational age because miscarriages that occur before 14 weeks frequently reflect a fetal death that happened a week or two earlier (174).
34.4.1 Chromosome Abnormalities
Although 60–80% of first-trimester losses are the result of a chromosome abnormality, only 10–24% of second-trimester losses and 5% of third-trimester stillbirths are associated with chromosome abnormalities (175,176). In contrast, the incidence of chromosome abnormalities in live births is 0.5–0.6% (177) The types of cytogenetic abnormalities found in second- and third-trimester losses are similar to those seen in live births. The most common chromosome abnormalities observed in late pregnancy losses are trisomy 13, 18, 21, and monosomy X and other sex chromosome aneuploidy.
34.4.2 Maternal Anatomic Abnormalities
As stated earlier, uterine abnormalities have been asso-ciated with an increased rate of pregnancy loss. These losses generally occur in the second trimester or result in preterm delivery (141). These abnormalities, including Müllerian anomalies, cervical insufficiency and uterine leiomyomata, are discussed in greater detail earlier in this chapter.
34.4.3 Abnormal Serum Markers
First- and second-trimester serum biochemical mark-ers are widely used to screen for fetal aneuploidy. In the first trimester, low levels of pregnancy-associated plasma protein A (PAPP-A) and free beta-human cho-rionic gonadotropin (β-hCG) with or without increased nuchal translucency (NT) thickness in the presence of a normal fetal karyotype, have been associated with increased risk for second- and third-trimester pregnancy loss (132,178–180). In a series of 7932 patients undergo-ing first-trimester screening, Goetzl et al. (178) observed a pregnancy loss rate prior to 20 weeks gestational age of 1.4% for women with multiple of the median (MoM) val-ues for PAPP-A below the fifth percentile compared with 0.36% for MoM values in the normal range (adjusted
odds ratio (OR) = 2.8). With respect to second-trimester serum analyte screening, a study involving over 77,000 women showed that those with very low (<0.25 MoM) maternal serum alphafetoprotein (MSAFP) levels had increased risk for spontaneous abortion (RR = 12.5), pre-term birth (RR = 4.8), low birth weight (RR = 5.8) and neonatal death (RR = 1.9). Likewise, women with very high MSAFP levels (>2.5 MoM) also had increased risk for spontaneous abortion (RR = 15.1), preterm birth (RR = 2.2) and stillbirth (RR = 4.0) (181). There are no proven interventions to prevent adverse outcomes for women who are at increased risk based on abnormal maternal serum screening values or NT measurements. Current data suggest that women with serum analyte and NT values in the screen-negative range can be reas-sured that the risks for adverse pregnancy outcome are low (178,180,181).
34.4.4 Thrombophilic Disorders
As discussed earlier, in a number of observational and retrospective case-control studies, the thrombophil-ias and antiphospholipid syndrome have been associ-ated with placental insufficiency and increased risk for adverse pregnancy outcome. Several of these studies have shown an association between FVL and PGM mutations and second- and third-trimester stillbirth (98,182–184). In a prospective cohort study involving 67 women with antenatal fetal death, Simchen et al. found that 33 women (49.3%) had evidence of a placental cause for fetal death (fetal growth restriction, oligohydramnios, placental abruption, and/or histological placental abnor-mality). Thirty-six of the 67 women (53.7%) tested positive for at least one of the following thrombophil-ias: FVL, PGM or C677T MTHFR (182). In a retro-spective study of a cohort of 363 women with three or more consecutive early or late pregnancy losses, Lund et al. (185) found that the unadjusted live birth rate in the subsequent pregnancy was 46% in carriers of FVL or PGM mutations versus 63% in noncarriers of these mutations (p = 0.04). However, after adjusting for sig-nificant covariables, they found that this difference was no longer significant (185). In a systematic review and meta-analysis of 10 prospective cohort studies, Rodger et al. (184) found that women with FVL had an absolute risk of 4.2% for late pregnancy loss (OR = 1.52). Thus, it appears that women with FVL or PGM mutations have an increased relative risk for adverse pregnancy outcome including fetal death. However, the absolute magnitude of this increased risk is small.
34.4.5 Infection
Although infection does not appear to be a common cause of early pregnancy loss, there are data that suggest that maternal–fetal infection is associated with pregnancy
CHAPTER 34 Fetal Loss 13
loss in the second and third trimesters. A number of studies implicate bacterial colonization of the lower and upper genital tract as a cause of a significant proportion of preterm births (186–189). Approximately 10–12% of all births in the United States are preterm (<37 weeks gestation). Nearly half of all preterm births are associ-ated with spontaneous preterm labor and approximately a third result from premature rupture of membranes (186). An inverse relationship between the percentage of positive chorioamnion bacterial cultures and gestational age at delivery has been observed (190). In addition, pos-itive chorioamnion cultures have been reported in 73% of women with spontaneous delivery prior to 30 weeks compared with 21% in women with clinically indicated delivery prior to 30 weeks (190). Amniotic fluid levels of proinflammatory cytokines, particularly interleu-kin-6 (IL-6), have been shown to be higher in women with spontaneous preterm delivery than in those with indicated preterm delivery (191,192).
Bacterial vaginosis (BV) is a condition characterized by overgrowth of gram-negative and anaerobic bacteria resulting in a decrease in the number of beneficial hydrogen peroxide producing Lactobacillis species. The most common organisms seen in BV include Gardner-ella vaginalis, Bacteroides sp., M. hominis, and U. urea-lyticum. Studies have demonstrated a twofold increased risk of spontaneous preterm birth among women with BV (186,193). In a prospective cohort study involving 1916 pregnant women, Nelson et al. (189) found a two-fold increased risk of second-trimester pregnancy loss in women with high levels of BV-associated organisms and low levels or absence of vaginal Lactobacillis sp. in the first trimester. Although the presence of BV is a risk fac-tor for late pregnancy loss, it is important to recognize that not all women with BV have upper genital tract infection. In fact, the majority of pregnant women with BV actually deliver at term and clinical trails involving treatment for BV in women with this condition have not shown a decrease in the rate of preterm labor or delivery (194).
Viral infection, particularly with CMV and parvovirus B-19, has been associated with increased risk for second-trimester pregnancy loss (151,195,196). Johansson et al. (196) analyzed blood samples from women taken in early pregnancy for the presence of parvovirus B-19 and herpes viruses. They found that 11 of 234 women (4.7%) who had second-trimester losses and 10 of 270 women (3.7%) who had preterm birth (prior to 32 weeks) had parvovirus B-19 viremia. This was compared with parvo-virus B-19 viremia in 5 of 294 (1.7%) women who deliv-ered at term. These findings corresponded to adjusted odds ratio of 3.76 for second-trimester miscarriage and 2.66 for preterm birth <32 weeks. Data such as these suggest that women with viremia in early pregnancy have increased risk for late pregnancy loss. However, more data are needed to confirm this association (196).
14 CHAPTER 34 Fetal Loss
34.4.6 Recurrent Loss
While pregnancy loss itself is not uncommon, recurrent pregnancy loss, often defined as three or more losses, only affects 1–2% of couples (197), but may suggest some underlying mechanism. These are the families that most often seek medical intervention and make up a large proportion of those being studied to determine underlying causes of pregnancy loss. Empirical data shows that a history of pregnancy loss increases the risk of miscarriage at subsequent pregnancies (1,132), with the risk increasing from 12% without any prior history to 24% after one loss, 32% after three losses and 53% after six or more losses. This supports the idea that in some couples, it is not chance alone that is responsible for an unsuccessful pregnancy history. Although the likelihood of a successful pregnancy for such couples is generally better than 60% (197,198), many seek medical assistance to identify the issues involved, in the hopes of determining a strategy to alleviate the problem. There have been numerous possible causes of recurrent preg-nancy loss investigated, and while the literature on this subject is very extensive, many of the proposed causes of recurrent miscarriage have not been substantiated by carefully controlled research, including some of those that have become part of clinical practice in some arenas.
The majority of studies of couples with recurrent pregnancy loss have reported the same risk factors as demonstrated for sporadic losses. As mentioned earlier, the incidence of fetal chromosome abnormalities and the types of abnormalities observed are also very similar, although several studies have shown a higher incidence of chromosome abnormalities in abortuses from women with a history of pregnancy loss, possibly correlated with the older maternal ages in this group. Parental chromo-some rearrangements and other genetic factors (discussed earlier) can lead to recurrent fetal loss in individual families, while parental mosaicism is likely to be more of a factor for young women with recurrent loss. Yet, the most consistent difference observed between women with sporadic vs recurrent pregnancy loss appears to be maternal age and a history of prior loss.
Factors that do seem to influence recurrence risks include loss of a chromosomally normal fetus (199), loss after the first trimester, a history of preterm deliveries, infertility problems (200), and younger maternal age (165,200,201). In a Danish study of all reported pregnan-cies between 1978 and 1992, the overall rate of sponta-neous pregnancy loss was reported to be 13.5%, similar to most other studies (201). Within this study, the rate of spontaneous loss in women aged 20–24 years was only 8.9%, while the rate of loss at age 42 was 50%, with nearly 75% of pregnancies in woman 45 years of age and older resulting in a spontaneous loss. A high rate of loss in older women, about 50% in women over 40, was con-firmed in another study (165). Ironically, as a woman’s age at each subsequent pregnancy is more advanced, failure
to achieve successful pregnancies, and the delay involved, can contribute to the risk of loss. As seen earlier, increas-ing maternal age is accompanied by a higher likelihood of a chromosomally abnormal fetus, which may then be the explanation for subsequent losses. It is significant that younger women (<35 years of age) with recurrent preg-nancy loss tend to have a lower frequency of chromo-somally abnormal fetuses than age-matched peers with a single pregnancy loss (35). Thus, in these younger women with recurrent spontaneous abortions the investigation of other explanations of pregnancy loss is warranted. Other possibilities include endocrine/ endometrial abnormalities, uterine structural abnormalities, thrombophilic disorders, immune disorders, and occasionally parental chromo-some rearrangements or other genetic disorders.
34.5 EVALUATION AND MANAGEMENT OF RECURRENT ABORTION
Evaluation of a couple with recurrent pregnancy loss begins with a detailed history, physical examination and appropriate diagnostic studies. The history should include the pattern and gestational age at the time of each prior loss. Gestational age at the time of loss should be con-firmed, if possible, by ultrasound, serum hCG results and embryo/fetal pathology. If available, prior cytogenetic results are useful to determine whether the previous losses were due to a structural or numerical chromosome abnor-mality. The review of systems should include an assessment of endocrinologic and immunologic disorders. Physical examination and laboratory evaluation should be directed toward detection of parental balanced structural chromo-some abnormalities, uterine anatomical abnormalities, endocrinologic disorders, immunologic disorders, micro-bial infection, and inherited thrombophilias. Once etio-logic factors are identified, a plan of management should be implemented based on current scientific evidence. A suggested plan for evaluation and management of recur-rent early pregnancy loss is shown in Table 34-1.
Psychologic support is often needed for couples with recurrent pregnancy loss. Recurrent miscarriage may lead to feelings of anger, guilt and depression. It may be helpful to refer couples for grief counseling or to suggest that they participate in support groups before attempt-ing a subsequent pregnancy. As noted earlier, supportive care and close monitoring of subsequent pregnancies has been reported to be associated with a greater likelihood of successful outcome.
34.6 CONCLUSIONS
Pregnancy loss, particularly when it is recurrent, is an important problem for patients and their clinicians, largely because of the variety of factors that have been proposed to be involved, although only a few of these have been confirmed by evidenced-based investiga-tion (Table 34-5). The single most common cause of
pregnancy loss is the presence of a chromosome abnor-mality in the fetus, particularly if the loss occurs early in the pregnancy. As these abnormalities are the result of random events that occur during meiosis and are highly correlated with maternal age, little follow-up or inter-vention may be indicated for these women, other than the reminder that as a woman ages, her risk of both chro-mosomally abnormal fetuses and pregnancy loss will increase. Therefore, karyotype analysis of POC should be a critical part of the evaluation of pregnancy loss, as the observation of a fetal chromosome abnormality would usually preclude the need for additional investigation. It would also serve to identify that population of woman with chromosomally normal fetal losses, in whom other factors may be contributing to recurrent pregnancy loss and in whom additional studies are indicated. These could include investigation of uterine abnormalities and evaluation of antiphospholipid antibodies or conditions that predispose to thrombosis, where potential therapies exist. Limiting clinical research studies to women in this population group should facilitate the evaluation of the efficacy of various therapeutic interventions. In the small population of couples in which parental chromosome abnormalities or other genetic disorders are detected, IVF and preimplantation prenatal diagnosis may help the couple achieve a successful pregnancy outcome. Predict-ing the likelihood of a successful pregnancy in a couple with recurrent pregnancy loss is complex. Factors to consider are the number of prior losses, the gestational age at the time of loss, cytogenetic findings, the patient’s medical history, and results of appropriate diagnostic studies. As noted earlier, if no underlying factors are dis-covered, many couples will eventually have a successful pregnancy with supportive care alone. The temptation to prescribe unproven treatments should be resisted, even if the couple is highly motivated and willing to “try anything.” Careful monitoring of the patient’s emo-tional status is important because patients with recur-rent pregnancy loss often experience anxiety, anger and depression. Referral for grief counseling or psychiatric care should be individualized based on the patient’s level of well-being.
CROSS REFERENCES
Chromosomal Basis of Inheritance; Cytogenetic Analy-sis; Prenatal Screening for Neural Tube Defects and
TABLE 34-5 Factors Definitively Associated with Early Pregnancy Loss
Aneuploidy; The Genetic Basis of Female Infertility; Clin-ical Teratology; Down Syndrome and other Autosomal Trisomies; Sex Chromosome Abnormalities; Deletions and Other Structural Abnormalities of the Autosomes; Preclampsia; Common Genetic Determinants of Coagu-lation and Fibronolysis; Hemoglobinopathies and Thal-assemias; Autoimmunity: Genetics and Immunological Mechanisms; Systemic Lupus Erythematosus; Thyroid Disorders; Diabetes Mellitus; Disorders of the Gonads, Genital Tract and Genitalia.
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RELEVANT WEB SITES
OMIM On Line Mendelian Inheritance in Man: http://www.ncbi.nlm.nih.gov/omim.
