Abortion, Placentas of Trisomies, and Immunologic Considerations of Recurrent Reproductive Failure
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21 Abortion, Placentas of Trisomies, and Immunologic Considerations of Recurrent Reproductive Failure For the present discussion, an abortion or miscarriage Terms other than spontaneous abortion (involuntary) is designated a conceptus that is expelled before the have been employed, and these have often confused 20th week of gestation. That is important to state at the the general abortion issue: “therapeutic abortion” (TAB; outset, as the pathologic features of failed pregnancies electively terminated), “missed” (retained for more differ markedly in specimens obtained later in gestation. than 8 weeks after embryonic death), “criminal” (illegally In the United States, terminations before 20 weeks con- instrumented), “habitual,” and “recurrent” abortions, and stitute abortions; later gestations are premature deliver- other terms designate specific entities. Not all of these ies. A pregnancy of 20 weeks is legally at the dividing definitions are universally accepted, and there is cogent line; it is a gestation with an “embryo” (that may be argument that the term “missed abortion” should be treated as a surgical specimen); later it is a “fetus,” whose abandoned (Pridjian & Moawad, 1989). It is best to clarify examination constitutes an autopsy. The terminology the specific nomenclature before one compares data employed in publications and statistics differs widely and from different institutions or countries. A useful method it is not the same in different countries. For instance, for categorization of abortion specimens was provided Vogel in Germany (1969, 1992) considered an abortion by Fujikura et al. (1966). They divided specimens into to be an expelled fetus of less than 1000 g. He differenti- groups with and without embryos, those with ruptured ated between embryonic and fetal (15–28 weeks) abor- and unruptured sacs, and included the degree of the com- tion. In many countries, legal viability is considered to pleteness of the specimen. In their experience, 22% were be attained only at 28 weeks of gestation, when the fetus classified as incomplete, and most (35.8%) had a normal has attained approximately 1000 g in weight; but that embryo or fetus. An embryo may be considered to be a is not so in the United States. Byrne et al. (1985), in a specimen with a crown–rump (CR) length of up to 30 mm study of early fetal deaths, considered all specimens of (less than 9 weeks), and a fetus may be considered an less than 28 weeks’ gestation. For these reasons it is unborn conceptus greater than 30 mm CR (Moore, 1982, difficult to place the studies of Vogel (1969, 1992) into 1994). When only incomplete specimens are available, it context with current terminology. Hutchon (1998) has been most practical to determine fetal age from mea- reviewed the complex terminology of this topic and surements of fetal foot length. Other extensive consider- proposed (with concurrence of a British study group ations of classification and specimen examination are laid on terminology) that the term abortion be replaced out in detail by Kalousek et al. (1990). Hern (1984) cor- with miscarriage, for all types under discussion. Most related various fetal measurements with gestational age truly spontaneous abortions occur before 12 weeks of in 1000 specimens and provided excellent tables from gestation and a majority is due to chromosomal errors which reasonably exact age determination is possible. in the conceptus. Relatively few really spontaneous “Threatened abortions” are represented by those clinical abortions occur in the period from 12 to 20 week’s cases in which vaginal bleeding occurs in the first trimes- gestation. Thereafter, between 20 and 30 weeks, another ter. Weiss et al. (2004) have reviewed a large study of this type of premature spontaneous termination becomes phenomenon and found that the amount of bleeding cor- prevalent, that which is primarily due to ascending responds to different gestational entities such as pre- infection with chorioamnionitis. Infection is relatively eclampsia, spontaneous abortion, abruptio, etc. uncommon before 20 weeks. These are fundamentally Spontaneous abortions are common. Despite this fre- different processes with also vastly different pathologic quency, patients often do not understand its nature, and, findings. especially when recurrent abortions occur, they find little 762 Abortion, Placentas of Trisomies, and Immunologic Considerations of Recurrent Reproductive Failure 763 comfort from consulting their physician. For that reason, (1988) have criticized some of these results and gathered Cohen (2005) has produced an excellent volume that the following figures from four studies: comprises nearly all that needs to be known about the topic, especially for the parturient. The exact frequency No. of losses No. of Risk of loss in with which pregnancy failure occurs spontaneously has recognized recognized been debated and our understanding of its pathogenesis Subclinical Clinical pregnancies pregnancies has undergone remarkable changes in recent years. Its 43 18 154 11.7 chromosomal causes are nicely reviewed by Cohen (2002), 7 11 85 12.9 and Clouston et al. (2002) have examined the chromo- 50 14 102 13.7 somal errors in 438 human blastocysts. Of these, 3% were 67 6 41 14.6 polyploidy (mostly tetraploid), 29% were diploid/tetra- ploid mosaics, and 68% were diploid and included a Most spontaneous abortions occur before 12 weeks of variety of trisomies. Trauma is no longer considered to be pregnancy, and chromosomal errors are their most prom- a common cause of abortion. Hertig and Sheldon (1943) inent cause but the exact mechanism of the abortion found only one set of twins whose abortion was probably event is still disputed. A recent review by Jauniaux and caused by external trauma among the 1000 miscarriages Burton (2005) suggested that oxidative stress may consti- they studied. “Internal trauma” was incriminated in 22 tute an important aspect of spontaneous abortions. They cases. Published figures on the incidence of abortion argued that because trophoblastic ingrowth of maternal depend largely on the method of sampling a population. vessels is reduced in spontaneous abortion specimens, an When prospective studies of complete populations are earlier true perfusion of the intervillous space occurs that done so as to include also all those pregnancies that give then results in trophoblastic damage. Numerous other few or no clinical symptoms of pregnancy, it is found that factors are also evaluated in their comprehensive review. nearly 50% of conceptions terminate in abortion sponta- In a study of amniocentesis results over 20 years of neously. For example, Miller et al. (1980) collected urine women age 35 or more, Caron et al. (1999) found that of 197 women who were wishing to conceive. They began 1.79% had chromosomal errors, with trisomies and struc- the collection at ovulation to obtain the earliest evidence tural rearrangements prominent findings. Stern and of pregnancy and investigated 623 menstrual cycles. Their Coulam (1992) found in a study of recurrent abortions diagnosis of pregnancy was made with sensitive radioim- that the reduction in sonographic size of the “fetal pole” munoassays for b-human chorionic gonadotropin (b- and differences in fetal heart rate activity at 6 weeks hCG). There were 152 conceptions, with a pregnancy loss allowed great accuracy in anticipating an abortion. The of 43%; but only 14 of the abortions were recognized hypoplasia of the placenta, so often observed and that clinically as being pregnancies. The other 50 patients presumably correlates with the decreased hCG secretion merely had a rise of urinary hCG level from which and hence progesterone support of the decidua, is an implantation was inferred. McLean (1987) reviewed accepted possibility. A specific inquiry into the small other studies that arrived at similar figures. They cited gestational sac (sonographically) and other gestational that approximately 50% of implanted pregnancies parameters was undertaken by Dickey et al. (1992). They aborted spontaneously, and most of them were clinically found small gestational sacs more often in chromosom- unrecognized. Additionally, there are probably concep- ally normal abortuses. It has recently been suggested that tuses that vanish even before implantation. Wilcox et “illegal” blood flow into the intervillous space at an early al. (1988) identified 31% spontaneous abortions of 707 gestational age may equally be of importance in causing cycles collected from 221 women. In a subsequent evalu- spontaneous abortions (e.g., Jauniaux & Burton, 2005). ation of early abortions, Wilcox et al. (1999) determined Schaaps and Hustin (1988) and Hustin et al. (1988) had from hormone studies that optimal implantation occurs earlier reviewed the interesting evidence of early tropho- between days 8 and 10 after ovulation. Of 189 pregnan- blast invasion. From their findings they concluded that cies, 75% went at least 6 weeks past last menses, 25% massive trophoblastic infiltration of uteroplacental arter- ended in early losses. Conversely, Regan and Rai (2000) ies essentially occludes these vessels before 12 weeks’ indicated that 78% of fertilized ova fail to result in a live gestation. This trophoblastic proliferation, they suggested, birth. They analyzed all aspects of miscarriage, especially permits only plasma filtrate to circulate in the intervillous recurrent abortion, and suggested that in the latter cate- space, at least in early gestation. It is apparently for this gory, 50% occur by chance. They dedicated