First and Second Trimester Pregnancy Loss

First and Second Trimester Pregnancy Loss

Jennifer Pogoriler, M.D., Ph.D.

Theonia K. Boyd, M.D.*

*Based upon the prior edition chapter by Deborah E. McFadden

Pathologic examination of the products of embryos and fetuses, both from spontaneous abortions (SAbs) and terminations of pregnancy, has become increasingly important. While such examination was once performed primarily for the purpose of furthering scientific understanding of prenatal human development, the practical medical applications of this knowledge have become clear and now form an integral part of the medical assessment and management of fertility issues (1,2,3,4,5). As an understanding of the factors involved in successful pregnancies has developed and as patient demand for information has increased, the role of pathologic examination has grown. Increased use of assisted fertilization techniques has heightened the interest of physicians and patients alike in understanding why pregnancies fail. This chapter will address the examination of disorders encountered in those pregnancies that end spontaneously in the first and second trimesters of gestation; the pathology of fetuses delivered after pregnancy termination after prenatal ultrasound diagnosis is beyond the scope of this chapter.

It is recognized that many conceptions do not end in live births but, rather, that there is a high rate of spontaneous loss, especially early in gestation. It is estimated that 10% to 20% of recognized pregnancies end as SAbs, with most losses occurring in the first trimester (first 12 to 14 weeks of gestation). With the demonstration of fetal cardiac activity, the miscarriage rate drops to approximately 3% to 12% (6). In a study of women with a normal prenatal visit at 6 to 11 weeks of gestational age (GA), the risk of subsequent SAb was 1.6% or less, considerably lower than for pregnancies overall (7). After the first trimester, approximately 1% to 2% of pregnancies are spontaneously aborted (8). The incidence of stillbirth at term gestation is in the order of 0.1% to 0.5%. These loss rates that persist throughout gestation, together with changing or changed societal approaches and expectations of pregnancy such as delaying childbearing until later in a woman’s reproductive life and increased access to assisted reproduction methods, have led to an intense interest in understanding the cause of pregnancy loss and the implications for future reproductive success.

GA refers to the number of weeks since the last menstrual period (equivalent to menstrual dates), while developmental age (DA) or conceptual age (CA) refers to the age as determined from the time of fertilization, generally considered as approximately 2 weeks after the last menstrual period. Embryos are assessed by developmental features that correlate with age, usually given as DA. Thus, in a normal gestation, GA is DA plus 2 weeks.

The first trimester of pregnancy is the period of implantation and embryogenesis, with the completion of embryogenesis by 8 weeks of DA (10 weeks of GA). Upon completion of embryogenesis with development of all organ systems, the conceptus is referred to as a fetus. Definitions of fetus and infant vary with locale; in Canada, a fetus is considered an infant once it has reached the GA of 20 weeks or is liveborn at any GA. In the United States, by contrast, the living intrauterine conceptus is referred to as a fetus until the time of live birth. Stillbirth is defined as delivery of a deceased conceptus at or after 20 weeks of GA.


It is well recognized that the major causes of early SAb are lethal chromosomal abnormalities, which are usually aneuploid (any karyotype that deviates from two haploid sets of 22 autosomes and one sex chromosome, with each haploid set contributed by one parent) (9). The use of techniques such as comparative genomic hybridization (CGH) and quantitative fluorescence-polymerase chain reaction (QF-PCR) to supplement conventional cytogenetic analysis has increased the detection of chromosome abnormalities because these
techniques do not require cell culture and can address the issue of maternal cell contamination. Numerous studies have shown that at least half of early SAbs are chromosomally abnormal when routine cytogenetics is performed. Array CGH may be used in cases in which tissue culture for cytogenetic analysis has failed or in which maternal cell contamination is suspected (10,11,12). More recent studies of preimplantation blastomeres in in vitro fertilization (IVF) patients have shown that even in young healthy couples, fewer than 10% of embryos have a normal karyotype in all blastomeres (13), although it is unclear if this is due to IVF or reflects a typical state of chromosomal instability in early embryonic life.

The distribution of chromosome abnormalities is consistent between various studies, with trisomy accounting for half of all chromosomally abnormal SAbs, polyploidies and monoploidies (primarily monosomy X) each accounting for 10% to 15%, and structural rearrangements accounting for approximately 5%. (14,15). Trisomy for two chromosomes (double trisomy) is seen in only 3% of the chromosomally abnormal early SAbs. Trisomies for chromosomes 16, 21, and 22 are most common in early SAbs. The structural abnormalities are an important subgroup because of the possibility that they have arisen from a parent who carries a rearrangement predisposing to an unbalanced karyotype in the offspring. Studies of couples who have had recurrent miscarriages show that 5% have balanced rearrangements such as reciprocal translocations (16). These individuals have an increased risk of conceiving chromosomally abnormal pregnancies as well as recurrent miscarriage (17), with the actual risk depending on the type of rearrangement and the chromosomes involved (18). Although the presence of a balanced translocation predicts a risk of increased miscarriage in future pregnancies, the risk of a liveborn infant with a translocation is extremely low, and the proposed benefit of preimplantation genetic diagnosis is to shorten the interval between pregnancies, in order to achieve a successful outcome (19) rather than to improve the overall live birth rate.

With respect to trisomic conception, the most common subset of nonviable aneuploidies, studies of parental origin have demonstrated that the largest proportion of trisomy is maternally derived. There is a strong positive correlation with maternal age, meaning that the risk of conceiving a trisomic conceptus rises with increasing maternal age (20). Hypotheses to explain this finding include abnormal chromosomal crossover, altered chromatin cohesion, and altered DNA damage checkpoints. Trisomy affects 3% of pregnancies in 25-year-old women but occurs in 35% of pregnancies in women aged 42 years (21). Most trisomies are the result of errors in meiosis I (22), although this varies for individual chromosomes. For example, trisomy 18 is more typically the result of errors in the second meiotic division, while trisomy 21 is predominantly the result of first meiotic division errors.

With the predominance of SAbs attributable to aneuploidy, it is clear that in order to ensure clinical relevance of SAb evaluations, the examination should include determination of karyotype, particularly in recurrent pregnancy loss. In the event that the examination proves normal, with normal karyotype and normal villus histology, management of persons having recurrent SAbs shifts and other etiologies for pregnancy loss must be considered (23). The investigation of those who have had chromosomally normal miscarriages with no other pathology is dependent upon the proposed nonchromosomal mechanisms of pregnancy loss. These proposed associations include exogenous environmental exposures, uterine abnormalities (24), skewed X-inactivation (25,26), disorders of endocrine function, immune disorders including conditions with autoantibodies, and thrombophilic conditions (15). The roles of these factors in miscarriage remain under investigation, and the relative significance of each has not been established with certainty. Prospective cohort studies have not shown an association between single inherited thrombophilia mutations and miscarriage, although multiple mutations may increase risk (27,28,29,30). Prophylactic anticoagulant treatment has not been shown to improve outcomes in patients with recurrent miscarriages and inherited thrombophilias, and screening for these conditions is therefore not currently recommended (31), although this practice remains controversial (30). There is less controversy about the role of antiphospholipid antibody in recurrent pregnancy loss. Antiphospholipid antibodies are found more often in women who have recurrent miscarriages (RSAb) than in other women, although the mechanism by which an antiphospholipid antibody causes pregnancy loss is not definitively known. It is speculated that it may be due to interference with trophoblast function and thus the establishment of successful implantation, mediated by early-onset inadequate decidual arteriolar perfusion, and/or due to maternal/gestational interface inflammation (32). There are no specific pathologic features identified in the first trimester SAb from women who are positive for this antibody. Later findings seen in a subset of patients are also nonspecific but include those changes seen in other causes of uteroplacental malperfusion including infarction, increased intervillous fibrin, and terminal villous hypoplasia (33,34,35). Current guidelines recommend screening in patients with prior venous thromboembolism, with one fetal loss or with multiple embryonic losses. Treatment with prophylactic anticoagulation may improve outcome in these patients (36). With changing reproductive patterns, such as women starting their families later in life and having fewer children, there is enhanced societal desire to diagnose and manage causes of miscarriage. Given that cytogenetic abnormalities account for the majority of first trimester abortions, it has been suggested that the evaluation of first trimester SAb with cytogenetic analysis may prove more cost effective than a standard battery of tests such as thyroid function tests, endometrial biopsy, or thrombophilia testing (37). Pathologic examination also serves to identify those conditions not associated with abnormal karyotype that may require additional investigation or treatment to increase the likelihood of successful
pregnancy and to diagnose conditions in which there is a risk of neoplasia, as with molar gestations and their attendant risk of transformation to gestational trophoblastic neoplasia (GTN) (1).


Indication for Cytogenetic Analysis

Given that chromosome abnormality accounts for the majority of first trimester SAbs, an argument could be made for performing cytogenetic analysis on all cases. To assist in the reproductive counseling regarding cause of the SAb and risks for recurrence, karyotype is a vital piece of information. Where embryo-pathology examination was once performed only in cases of recurrent SAbs, changes in reproductive patterns and practices have altered, resulting in a broader range of cases referred for embryo-pathologic examination. Those who treat women who have had difficulty conceiving or who have had previous miscarriage(s) are anxious to know whether the pregnancy failure was the result of chromosome abnormality or if there is perhaps another etiology necessitating further investigation. Increasingly, assisted reproductive technologies (ARTs) such as IVF or intracytoplasmic sperm injection (ICSI) are utilized. There are concerns that ARTs are associated with an increased incidence of chromosome abnormalities at prenatal diagnosis and at birth, specifically for sex chromosome abnormalities in pregnancies that are the result of ICSI (38,39). However, many small studies have found a high rate of chromosomal abnormalities in both ART and naturally conceived miscarriages, and a recent meta-analysis of case-controlled studies of chromosomal abnormalities in first trimester miscarriages showed no significant differences between either IVF or ICSI and natural conception, with the risk of abnormalities increased in older women in all groups (40).

Until the natural history of ART pregnancies is delineated, the use of these technologies should be considered as an indication for cytogenetic analysis in cases of SAb. In some laboratories, the fact that the majority of first trimester SAbs are the result of chromosome abnormality is sufficient indication to perform cytogenetic analysis of all cases examined morphologically. In other laboratories, constraints imposed by funding structures may impose the necessity of specific clinical indication before cytogenetic studies will be funded. These other indications include a history of recurrent miscarriages (variably defined as two to three or more losses), abnormal villus morphology, abnormal or normal embryo, parental chromosome rearrangement, and maternal age 35 years or greater.