Spontaneous abortion: Risk factors, etiology, clinical manifestations, and diagnostic evaluation Authors Togas Tulandi, MD, MHCM

Haya M Al-Fozan, MD Section Editors Deborah Levine, MD Robert L Barbieri, MD Deputy Editor Sandy J Falk, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Mar 2013. | This topic last updated: jul 17, 2012. INTRODUCTION Spontaneous abortion (SAb), also known as miscarriage, refers to a pregnancy that ends spontaneously before the fetus has reached a viable gestational age [1]. The World Health Organization defines it as expulsion or extraction of an embryo or fetus weighing 500 g or less from its mother. This typically corresponds to a gestational age of 20 to 22 weeks or less [2]. The term "fetus" will be used throughout this discussion, although the term "embryo" is the correct developmental term at 10 weeks of gestation. Diagnostic issues relating to SAb will be reviewed here. Recurrent abortion and management issues are discussed separately. (See "Evaluation of couples with recurrent pregnancy loss" and "Spontaneous abortion: Management".) INCIDENCE SAb is the most common complication of early pregnancy [1]. The frequency decreases with increasing gestational age. Eight to 20 percent of clinically recognized pregnancies under 20 weeks of gestation will undergo SAb; 80 percent of these occur in the first 12 weeks of gestation [3-5]. The overall risk of SAb after 15 weeks is low (about 0.6 percent) for chromosomally and structurally normal fetuses, but varies according to maternal age and ethnicity [6]. Loss of unrecognized or subclinical pregnancies is even higher, occurring in 13 to 26 percent of all pregnancies [3-5,7-9]. Early pregnancy losses are unlikely to be recognized unless daily pregnancy tests are performed. A study that compared women's bleeding following a pregnancy loss before 6 weeks of gestation with their typical menstruation found that mean bleeding length following a pregnancy loss was 0.4 days longer than the woman's average menses and the amount of bleeding was light [10]. These data were obtained from studies such as the following representative examples: In a classic study in which daily urinary human chorionic gonadotropin (hCG) assays were determined, the total rate of pregnancy loss after implantation was 31 percent; 70 percent of these losses (22 percent of all pregnancies) occurred before the pregnancy was detected clinically [4]. In another study, daily urinary hCG assays were performed on 518 nulliparous, newly married women aged 20 to 34 years who were attempting to conceive and had no known infertility [5]. Of the 586 conceptions with known outcome, loss of a preclinical pregnancy occurred in 26 percent, loss of a clinically recognized pregnancy occurred in 8 percent, live birth occurred in 64 percent, with the remainder comprised of induced abortion, ectopic pregnancy, molar pregnancy, and stillbirth.

If preimplantation losses are considered, 50 percent of fertilized oocytes do not result in a live birth [11].

RISK FACTORS Numerous risk factors are associated with an increased risk of pregnancy loss: Age Advancing maternal age is the most important risk factor for spontaneous miscarriage in healthy women. The effect of maternal age on pregnancy outcome was illustrated in a review of over 1 million pregnancies of known outcome and with admission to a hospital [12]. The overall rate of SAb was 11 percent and the approximate frequencies of clinically recognized miscarriage according to maternal age were: age 20 to 30 years (9 to 17 percent), age 35 (20 percent), age 40 (40 percent), and age 45 (80 percent) [12]. Previous spontaneous abortion Past obstetrical history is an important predictor of subsequent pregnancy outcome. The risk of miscarriage in future pregnancy is approximately 20 percent after one miscarriage, 28 percent after two consecutive miscarriages, and 43 percent after three or more consecutive miscarriages [13]. By comparison, miscarriage occurred in only 5 percent of women in their first pregnancy or in whom the previous pregnancy was successful. Smoking Heavy smoking (greater than 10 cigarettes per day) is associated with an increased risk of pregnancy loss (relative risk 1.2 to 3.4) [14-18]. This association is more pronounced when controlling for other causes of pregnancy loss, such as limiting the analysis to chromosomally normal abortuses [19-21]. The mechanism is not known, but may be related to vasoconstrictive and antimetabolic effects. Paternal smoking may also increase the risk of pregnancy loss [22]. Smoking cessation should be recommended for its overall health benefits (see "Smoking and pregnancy" and "Patterns of tobacco use"). Alcohol Observational studies have generally, but not consistently, reported that moderate to high alcohol consumption increases the risk of SAb [3,23-30]. As an example, in one study there was an increased risk of miscarriage in women who drank more than 3 drinks per week in the first 12 weeks of pregnancy [23]. Interpretation of studies of alcohol use in pregnancy is complicated by potentially inadequate adjustment for confounders and underreporting of alcohol use. Women planning pregnancy should avoid alcohol consumption since alcohol is a known teratogen and a safe level of alcohol intake has not been established at any stage of pregnancy. (See"Alcohol intake and pregnancy" and "Overview of illicit drug use in pregnant women".) Gravidity Some studies have shown an increased risk of miscarriage with increasing gravidity [31,32], while others have not [33-35]. Possible reasons for this association include (1) reproductive compensation behavior (pregnancy failure is likely to be associated with repeated attempts at conception resulting in higher gravidity) and (2) short interpregnancy intervals in multigravid women. (See "Interpregnancy interval and pregnancy outcome".) Cocaine Use of cocaine is associated with preterm birth, and may also be a risk factor for spontaneous abortion [18]. In one study of 400 women who had a SAb and 570 controls who remained pregnant through at least 22 weeks of gestation, the presence of cocaine in hair samples was independently associated with an increase in the occurrence of spontaneous abortion after adjustment for demographic and drug-use variables (OR 1.4; 95% CI 1.0-2.1) [18]. (See "Overview of illicit drug use in pregnant women".) Nonsteroidal antiinflammatory drugs The use of nonsteroidal antiinflammatory drugs (NSAIDs), but not acetaminophen, may be associated with an increased risk of miscarriage if used around the time of conception [36,37]. The postulated mechanism is that prostaglandin inhibitors interfere with the role prostaglandins play in implantation, thus potentially leading to abnormal implantation and pregnancy failure [38-41]. Although data are sparse, it is reasonable to suggest that women who are trying to conceive should consider avoiding use of NSAIDS to

minimize the risk of miscarriage, especially when alternative drugs (eg, acetaminophen) are available. Fever Fevers of 100F (37.8C) or more may increase the risk of miscarriage, but the only two large studies have been contradictory and inconclusive. One study of women having euploid abortions, aneuploid abortions, and delivering at 28 weeks of gestation or later (controls) hypothesized that if fever was an antecedent (rather than a symptom) of SAb, there would be an association between fever and euploid, but not aneuploid, abortions [42]. Analysis of data supported this hypothesis: fevers were significantly more frequent among women with euploid abortions than among controls (18 versus 7 percent), but not more frequent among women with aneuploid abortions. Their hypothesis was also strengthened by the observation that the risk of abortion was highest proximate to the febrile episode: the ORs for abortion when fever occurred in the same calendar month, one month before, or two or more months before a euploid abortion were 6.0, 3.3, and 1.4, respectively. By comparison, a second series interviewed over 24,000 Danish women in the first 16 weeks of pregnancy and obtained information on the number of fever episodes, highest temperature, duration, and gestational age at occurrence [43]. This information was subsequently linked to a pregnancy outcome registry. Fever occurred in 18.5 percent of participants. There was no association between fever or any specific fever characteristic and first, second, or third trimester fetal death, before or after adjustment of risk factors. However, the low rate of first trimester pregnancy loss (2.3 percent) suggests some women with spontaneous abortions were not included, potentially masking an effect of fever on early loss.

Caffeine Meta-analyses of controlled studies have generally reported an association between caffeine intake and spontaneous abortion, primarily at high levels of consumption. However, these studies have multiple limitations, including selection and recall bias, confounding, issues pertaining to exposure measurement (ie, inability to accurately measure caffeine intake since it depends upon the size of the cup, brand of coffee, and brewing method), as well as failure to account for fetal karyotype, caffeine metabolism, timing of fetal demise, and the possibility that an effect of caffeine may be gestational age-specific. The mechanism for the increased rate of SAb with high caffeine intake might be related to maternal metabolism and clearance of this substance. These issues are discussed in detail separately. (See "The effects of caffeine on reproductive outcomes in women".) Prolonged ovulation to implantation interval Early losses have also been related to a prolonged interval (ie, >10 days) between ovulation and implantation [44]. Such delays might result from fertilization of an older ovum, delayed tubal transport, or abnormal uterine receptivity. Prolonged time to pregnancy Observational studies have reported that prolonged time to achieving pregnancy correlates with an increased risk of miscarriage [45-47]. Low-folate level A well-designed, population-based, case-control study showed low plasma folate levels (2.19 ng/mL [4.9 nmol/L]) were associated with an increased risk of SAb at 6 to 12 weeks of gestation, but only when the fetal karyotype was abnormal [48]. Low folate levels with normal fetal karyotype and high folate levels had no such adverse effect. In this population, less than 5 percent of women received folate supplement. Whether low folate levels increase the risk of abnormal karyotype in the embryo and subsequent abortion is under investigation. Some investigators have suggested that maternal polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTRR) genes may increase the risk of meiotic

nondisjunction. (See "Congenital cytogenetic abnormalities", section on 'Trisomy 21 (Down syndrome)'.) There is no evidence that vitamin supplementation prevents miscarriage [49]. There is no specific evidence that folate supplementation reduces the risk of miscarriage in women with hyperhomocysteinemia, although this has been suggested [50]. However, folate supplements are routinely recommended for all pregnant women anyway for prevention of neural tube defects. Maternal weight Prepregnancy body mass index less than 18.5 or above 25 kg/m2 has been associated with an increased risk of infertility and SAB [51-54]. (See"Optimizing natural fertility in couples planning pregnancy" and "The impact of obesity on fertility and pregnancy".) Celiac disease Untreated celiac disease may be associated with a higher risk of SAb. (See "Definition and etiology of recurrent pregnancy loss", section on 'Celiac disease'.) ETIOLOGY In one-third of imaging studies at or before 8 weeks of gestation, no embryo or yolk sac is seen in the gestational sac. In the two-thirds of cases in which an embryo is found, approximately 50 percent are abnormal, dysmorphic, stunted, or too macerated for examination [55]. Abnormal embryos may result from chromosomal abnormalities or exposure to teratogens. Chromosomal abnormalities Chromosomal abnormalities account for approximately 50 percent of all miscarriages. Most of these abnormalities are aneuploidies; structural abnormalities and mosaicism are responsible for relatively few abortions. The earlier the gestational age at abortion, the higher the incidence of cytogenetic defects: the incidence of abnormal fetal karyotype is 90 percent in anembryonic products of conception, 50 percent for abortuses at 8 to 11 weeks of gestation, but decreases to 30 percent of abortuses at 16 to 19 weeks [56]. The frequency and types of chromosomal abnormalities in early pregnancy loss were illustrated in a review of 8841 spontaneous abortions in which 41 percent had chromosomal abnormalities [57]. The most frequent types of abnormalities detected were: Autosomal trisomies 52 percent Monosomy X 19 percent Polyploidies 22 percent Other 7 percent

Trisomy 16 is the most common autosomal trisomy and is always lethal. Most chromosomal abnormalities in the embryo arise de novo. Rarely, these defects are inherited as a consequence of parental karyotypic abnormalities, such as balanced translocations. (See "Definition and etiology of recurrent pregnancy loss", section on 'Genetic factors'.) Genetic abnormalities not detected by conventional cytogenetic analysis (G-banded karyotype) account for an undefined proportion of spontaneous abortions. These abnormalities include small deletions and duplications and point mutations. Congenital anomalies Congenital anomalies are caused by genetic or chromosomal abnormalities, extrinsic factors (eg, amniotic bands), and exposure to teratogens. Potential teratogens include maternal disorders (eg, diabetes mellitus with poor glycemic control), drugs (eg, isotretinoin), physical stresses (eg, fever), and environmental chemicals (eg, mercury). (See "Genetic and environmental causes of birth defects", section on 'Teratogens' and "Principles of teratology".) Trauma Invasive intrauterine procedures/trauma, such as chorionic villus sampling and amniocentesis, increase the risk of abortion. In contrast, the early gestational age uterus is

generally protected from blunt trauma to the maternal abdomen [58]. (See "Chorionic villus sampling: Risks, complications, and techniques" and "Diagnostic amniocentesis".) Host factors Pregnancy loss may also be related to the host environment. As an example, congenital or acquired uterine abnormalities (eg, uterine septum, submucosal leiomyoma, intrauterine adhesions) can interfere with optimal implantation and growth [59]. (See "Reproductive issues in women with uterine leiomyomas (fibroids)".) Acute maternal infection with any of a large number of organisms (eg, Listeria monocytogenes, Toxoplasma gondii, parvovirus B19, rubella, herpes simplex, cytomegalovirus, lymphocytic choriomeningitis virus [60]) can lead to abortion from fetal or placental infection. Maternal endocrinopathies (eg, thyroid dysfunction, Cushing's syndrome, polycystic ovary syndrome) can also contribute to a suboptimal host environment. Since corpus luteum progesterone production is an integral component of successful pregnancy, it is plausible that early pregnancy loss could be due to corpus luteum dysfunction; however, this is controversial. Some well-designed studies did not support this theory as they showed maternal serum progesterone levels proximate to implantation (a time when corpus luteum progesterone production is critical) were similar for continuing pregnancies and those subsequently lost [61,62]. The use of progesterone to distinguish between a nonviable (missed abortion or ectopic pregnancy) and a viable pregnancy when the location of the pregnancy is unknown is addressed separately. (See "Clinical manifestations, diagnosis, and management of ectopic pregnancy", section on 'Progesterone'.) The effect of thyroid disease and thyroid peroxidase antibodies on abortion risk is also reviewed separately. (See "Overview of thyroid disease in pregnancy".) A hypercoagulable state due to inherited or acquired thrombophilia and abnormalities of the immune system (eg, systemic lupus erythematosus, antiphospholipid syndrome) that lead to immunological rejection or placental damage are active areas of investigation. (See "Inherited thrombophilias in pregnancy" and "Obstetrical manifestations of the antiphospholipid syndrome".) Unexplained The etiology of abortion of chromosomally and structurally normal embryos/fetuses in apparently healthy women is unclear. As discussed above, genetic abnormalities not detected by standard karyotype analysis (small deletions and duplications and point mutations) account for an undefined proportion of spontaneous abortions. CLINICAL MANIFESTATION AND DIAGNOSIS Women who are actively in the process of having a spontaneous abortion usually present with a history of amenorrhea, vaginal bleeding, and pelvic pain. On examination, the cervix is open and the products of conception can be visualized in the vagina or cervical os, if they have not already been passed. The terminology for early pregnancy complications has not been standardized, thus variations in the terms used to describe these events are common [63]. As an example, a pregnancy in which no embryo is seen may be called an empty sac (previous terms included blighted ovum or anembryonic pregnancy) [63]. A missed abortion may be called an embryonic or early fetal demise, an early fetal loss, or a delayed or silent miscarriage. Patients prefer the term "miscarriage" to "abortion." Threatened abortion Bleeding through a closed cervical os in the first half of pregnancy is quite common and is termed threatened abortion. The bleeding is often painless, but may be accompanied by minimal/mild suprapubic pain. On examination, the uterine size is appropriate for gestational age and the cervix is long and closed. Fetal cardiac activity is detectable by ultrasound or Doppler examination if the gestation is sufficiently advanced. The exact etiology of

bleeding often cannot be determined and is frequently attributed to marginal separation of the placenta. The term "threatened" abortion is used to describe these cases because pregnancy loss does not always follow vaginal bleeding in early pregnancy, even after repeated episodes or large amounts of bleeding. In fact, 90 to 96 percent of pregnancies with both fetal cardiac activity and vaginal bleeding at 7 to 11 weeks of gestation will result in an ongoing pregnancy, with the higher success rate occurring at the later gestational ages [64]. A systematic review found a modest association (odds ratio 2) between first trimester bleeding and various adverse outcomes (eg, miscarriage, preterm birth, premature rupture of membranes, growth restriction, antepartum bleeding) later in pregnancy [65]. The prognosis is worse when the bleeding is heavy or extends into the second trimester [66-69]. As an example, in one large prospective series, the frequency of preterm delivery with no, light, or heavy first trimester bleeding was 6, 9.1 and 13.8 percent, respectively, and the frequency of spontaneous loss before 24 weeks of gestation was 0.4, 1.0, and 2.0 percent, respectively [66]. Of note, all of these pregnancies had cardiac activity at the time of enrollment at 10 to 14 weeks of gestation. Because these subjects were enrolled late in the first trimester and with sonographically confirmed fetal cardiac activity, women with very early bleeding that went on to miscarry had already been excluded. These findings were further supported by a subsequent populationbased study of almost 800,000 women, which also reported an association between first trimester bleeding in a woman's first pregnancy with recurrent bleeding in a second pregnancy [70]. No change in pregnancy management is indicated because of the low predictive value for adverse outcome and the lack of effective interventions. (See "Risk factors for preterm labor and delivery", section on 'Vaginal bleeding'.) Inevitable abortion When abortion is imminent, bleeding increases, painful uterine cramps/contractions reach peak intensity, and the cervix is dilated. The gestational tissue can often be felt or visualized through the internal cervical os. Complete and incomplete abortion When an abortion occurs before 12 weeks of gestation, it is common for the entire contents of the uterus to be expelled, thereby resulting in a complete abortion. Over one third of all cases are complete, rather than incomplete, abortions. If a complete abortion has occurred, the uterus is small and well contracted with a closed cervix, scant vaginal bleeding, and only mild cramping. After 12 weeks, the membranes often rupture and the fetus is passed, but significant amounts of placental tissue may be retained, leading to an incomplete abortion, also called an abortion with retained products of conception. On examination the cervical os is open, gestational tissue may be observed in the vagina/cervix, and the uterine size is smaller than expected for gestational age, but not well contracted. The amount of bleeding varies, but can be severe enough to cause hypovolemic shock. Painfulcramps/contractions are often present. Ultrasonographic diagnosis of an incomplete miscarriage or retained products of conception is problematic. Measurement of endometrial thickness and the appearance of the midline echo have been used to make these diagnoses, but there is no agreement on the appropriate cut-off for endometrial thickness (15 mm is commonly used) and no threshold has been proven to be reliable [71]. When heterogeneous material is present in the endometrial cavity, Doppler ultrasound can be helpful in distinguishing between retained products of conception and blood clot. If blood flow to retained placental tissue is visualized, then it is possible to make the diagnosis of retained

products of conception. However, if blood flow is absent, then either devascularized retained products of conception or blood clot could be present. Missed abortion A missed abortion refers to in-utero death of the embryo or fetus prior to the 20th week of gestation, with retention of the pregnancy for a prolonged period of time. Women may notice that symptoms associated with early pregnancy (eg, nausea, breast tenderness) have abated and they don't "feel pregnant" anymore; vaginal bleeding may occur. The cervix is usually closed. Septic abortion Common clinical features of septic abortion include fever, chills, malaise, abdominal pain, vaginal bleeding, and discharge, which is often sanguinopurulent. Physical examination may reveal tachycardia, tachypnea, lower abdominal tenderness, and a boggy, tender uterus with dilated cervix. Infection is usually due to Staphylococcus aureus, Gram negative bacilli, or some Gram positive cocci. Mixed infections, anaerobic organisms, and fungi, can also be encountered. The infection may spread, leading to salpingitis, generalized peritonitis, and septicemia. Most spontaneous abortions are not septic. Septic abortion is, however, a common complication of illegally performed induced abortion. Infrequently, septic abortion is related to foreign bodies (eg, intrauterine contraceptive device, laminaria), invasive procedures (eg, amniocentesis, chorionic villus sampling), maternal bacteremia, or incomplete spontaneous or legally induced abortion. Septic deaths related to Clostridium sordellii have been reported after medical termination of early pregnancy. (See"Mifepristone for the medical termination of pregnancy".) DIFFERENTIAL DIAGNOSIS The cardinal clinical sign of spontaneous abortion is vaginal bleeding. Bleeding in the first trimester may be light, heavy, intermittent, or constant and it may be painless or painful. The four major causes of bleeding early in pregnancy are: Physiologic (ie, believed to be related to implantation) Ectopic pregnancy Impending or complete miscarriage Cervical, vaginal, or uterine pathology

These entities are reviewed in detail separately. (See "Overview of the etiology and evaluation of vaginal bleeding in pregnant women".) Physical examination may reveal the source of bleeding (trauma, polyp, cervicitis, neoplasia). Transvaginal ultrasonography is the cornerstone of evaluation of bleedingand/or pelvic pain in early pregnancy (algorithm 1). It is used for distinguishing intrauterine from extrauterine (ectopic) and live from nonviable pregnancies. Ultrasound examination may also reveal that the patient has gestational trophoblastic disease. It is important when performing the transvaginal examination to use a high frequency transducer, as this will improve visualization of the yolk sac and early embryonic cardiac activity [72]. A single low human chorionic gonadotropin (hCG) concentration is only helpful if ultrasonography is nondiagnostic, ie, the site and viability of the pregnancy are not revealed. A single low hCG measurement is never diagnostic of a pregnancy problem; serial measurements are always necessary. Serial hCG measurements showing a falling beta-hCG concentration are consistent with both a nonviable intrauterine pregnancy and a spontaneously resolving ectopic pregnancy, but do not indicate whether the pregnancy is intrauterine or ectopic. The exception to this is the finding of a markedly high hCG, which suggests a molar pregnancy. The pattern of hCG change in normal and abnormal pregnancies and its correlation with ultrasound findings is

discussed in detail separately. (See "Clinical manifestations, diagnosis, and management of ectopic pregnancy", section on 'Human chorionic gonadotropin'.) Other hormone assays (eg, progesterone, estrogen, inhibin A, PAPP-A) are less useful. DIAGNOSTIC EVALUATION OF THREATENED ABORTION Clinical assessment Clinical assessment of women with vaginal bleeding and a closed cervix is insufficient for predicting prognosis because vaginal bleeding is common in the first trimester, occurring in 20 to 40 percent of pregnant women, and not always associated with impending abortion [73]. As discussed above, even heavy, prolonged bleeding can be associated with a normal outcome. Direct visualization of a dilated cervix or the gestational sac may be sufficient to diagnose an inevitable, incomplete, or complete abortion clinically; however, ultrasound examination can provide additional, sometimes unexpected, information such as the presence of a multiple gestation or retained products of conception. Loss of a previously detected fetal cardiac activity should raise suspicion that a missed abortion has occurred, but often symptoms occur well before the fetal heart has been detected with a hand-held Doppler device. Furthermore, inability to detect fetal cardiac activity with these devices can be due to incorrect placement of the device. Ultrasonography Ultrasonography is the most useful test in the diagnostic evaluation of women with suspected SAb [74]. There is no role for monitoring hCG levels once the presence of an intrauterine pregnancy has been established sonographically. A definite diagnosis of nonviable intrauterine pregnancy (missed abortion) can be made based upon either of the following criteria: Absence of embryonic cardiac activity in an embryo with crown-rump length greater than 5 mm [75]. Absence of a yolk sac when the mean sac diameter is 13 mm [72,76]. Absence of an embryonic pole when the mean sac diameter (average of diameters measured in each of three orthogonal planes) is greater than 25 mm measured transabdominally or greater than 18 mm by the transvaginal technique [77].

These measurements correspond to a gestational age of approximately 6 weeks. Serial examinations four to seven days apart are helpful to assess viability of the pregnancy when findings are equivocal or development appears to be lagging behind that expected by dating criteria. The normal sequential development during very early pregnancy, as noted sonographically, is shown in the table (table 1). (See "Prenatal assessment of gestational age".) Reassuring ultrasound findings Ultrasound findings of a normal yolk sac and fetal cardiac activity early in pregnancy are reassuring [64,78]. This was illustrated by a study of consecutive pregnancies that were followed until ongoing pregnancy or SAb could be documented [64]: The presence of a yolk sac between 22 and 32 days from in vitro fertilization (IVF) was associated with the development of fetal heart motion in 94 percent of pregnancies, and the absence of the yolk sac by 32 days after fertilization was always associated with a poor outcome. Valvular motion confirms a live pregnancy, but does not eliminate the possibility of future pregnancy loss. When embryonic heart motion was detected at 5 to 6 weeks of gestation in women less than 36 years of age, the risk of subsequent SAb was 4.5 percent; however, the risk of miscarriage despite previous detection of embryonic heart

activity increased to 10 percent in women aged 36 to 39 years and 29 percent in women greater than or equal to 40 years of age [64]. In women with recurrent pregnancy loss, the risk of spontaneous pregnancy loss after observation of embryonic heart activity remains high, about 22 percent [79]. Findings potentially predictive of pregnancy loss The following ultrasound findings are predictive of impending pregnancy loss. If any of these ominous findings are noted, then a repeat ultrasound examination in about one week is indicated because of the high likelihood of embryonic/fetal demise. When more than one ominous finding is present, the risk of subsequent abortion increases several-fold [80]: Abnormal yolk sac - An abnormal yolk sac may be large for gestational age, irregular, free floating in the gestational sac rather than at the periphery, or calcified. In one study, a yolk sac diameter more than two standard deviations of the mean for the menstrual age had a sensitivity, specificity, positive predictive value, and negative predictive value for pregnancy loss of 65, 97, 71, and 95 percent, respectively [81]. In another study, a mean sac diameter of 13 mm without a visible yolk sac was diagnostic of a nonviable gestation in 100 percent of cases [76]. Slow fetal heart rate - Embryonic heart rate below 100 beats per minute (bpm) at 5 to 7 weeks of gestation is slow [82-84]. In one study, the first trimester survival rate was 62 percent among 531 embryos with slow early heart rates (less than 100 bpm at less than 6.2 weeks, less than 120 bpm at 6.3 to 7.0 weeks) compared to 92 percent survival among 1501 embryos with normal heart rates [84]. Higher rates of pregnancy loss are associated with lower embryonic heart rates; survival is zero at heart rates below 70 bpm at 6 to 8 weeks of gestation [83,85-88]. An increased risk of first trimester embryonic demise persists in embryos with a slow heart rate at 6.0 to 7.0 weeks but normal heart rate at follow-up ultrasound at 8 weeks; one in four of these fetuses were lost [88]. If slow cardiac activity is observed, it is prudent to perform a follow-up sonogram (in five to seven days) to document loss of the cardiac activity before proceeding to dilatation and curettage. Small sac - Small mean sac size (MSS) is diagnosed when the difference between the MSS and crown-rump length (CRL) is less than 5 mm (MSS - CRL < 5). In one series, 15 of the 16 patients (94 percent) with normal embryonic heart rates and small sacs noted on first trimester sonogram went on to spontaneously abort compared to only 4 of the 52 control patients (8 percent) with normal sac sizes [89]. Other findings suggestive of poor pregnancy outcome are a sac with an irregular contour, mean sac diameter growth rate less than 1 mm/day, minimal decidualthickness/hypoechogenicity of the choriodecidual area/absent double decidual sac, and low sac position in the uterus [74]. Subchorionic hematoma A subchorionic hematoma is a risk factor for SAb (image 1 and image 2) [90]. A large subchorionic hematoma (ie, comprising at least 25 percent of the volume of the gestational sac) is concerning. A meta-analysis of seven comparative studies found that women with a subchorionic hematoma versus women without had a significantly increased risk of SAb (18 versus 9 percent; OR 2.18, 95% CI 1.29 3.68) [91]. There was also an increased risk of placental abruption (4 versus 1 percent; OR 5.71, 95% CI 3.91 8.33) and preterm premature rupture of membranes (4 versus 2 percent; OR 1.64, 95% CI 1.22 2.21). Increased risks of preterm labor and stillbirth appeared to be dependent upon the presence of vaginal bleeding. Pregnancy outcome associated with subchorionic hematoma appears to depend upon

location, with worse outcomes for retroplacental than marginal hematomas. The location, rather than the size, of a subchorionic hematoma is the most salient characteristic in terms of pregnancy outcome, in our experience. Women with retroplacental hematomas are more likely to have an adverse outcome than those that are marginal (only the margin of the placenta is separated) [92]. Data are mixed regarding whether increasing size of the hematoma increases the risk of adverse outcomes [93,94]. The only management option for subchorionic hematoma is expectant management. Some clinicians repeat an ultrasound in two weeks to confirm fetal viability and assess for change in size of the hematoma. This is often reassuring to the patient, but does not alter management. A subchorionic hematoma is not an indication for an evaluation for an inherited thrombophilia.

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain th th language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written th th at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient information: Miscarriage (The Basics)" and "Patient information: Threatened miscarriage (The Basics)") Beyond the Basics topics (see "Patient information: Miscarriage (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS Spontaneous abortion (SAb) (ie, a pregnancy that ends spontaneously before the fetus has reached a viable gestational age) is the most common complication of early pregnancy, occurring in 8 to 20 percent of clinically recognized pregnancies and a comparable number of preclinical pregnancies. (See 'Incidence' above.) The best documented risk factors for SAb are advanced maternal age, previous spontaneous abortion, and maternal smoking. (See 'Risk factors' above.) Most SAbs are due to structural or chromosomal abnormalities of the embryo. (See 'Etiology' above.) There are various stages and types of SAb. Women who are actively in the process of having a spontaneous abortion usually present with a history of amenorrhea, vaginal bleeding, and pelvic pain. The cervix is open and the products of conception can be visualized in the vagina or cervical os, if they have not already been passed. (See 'Clinical manifestation and diagnosis' above.) The cardinal sign of impending abortion is vaginal bleeding. Differential diagnosis included bleeding related to implantation, ectopic pregnancy, and cervical, vaginal, or uterine pathology. (See 'Differential diagnosis' above.)

Ultrasonography is the most useful test in the diagnostic evaluation of women suspected of SAb. A definite diagnosis of nonviable intrauterine pregnancy can be made if either of the following criteria is present: (1) absence of fetal cardiac activity in an embryo with crown-rump length greater than 5 mm or (2) absence of a fetal pole when the mean sac diameter is greater than 18 mm by the transvaginal technique. In the absence of these findings, other parameters (eg, slow fetal heart rate, abnormal yolk sac, small gestational sac) are predictive of pregnancy non-viability, but follow-up should be obtained. (See 'Diagnostic evaluation of threatened abortion' above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES

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