Timothy P. Canavan1, 2 and Joan M. Mastrobattista3, 4
Division of Ultrasound, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, 300 Halket Street, Pittsburgh, PA 15213, USA
The Center for Advanced Fetal Diagnostics, Magee Women’s Hospital, University of Pittsburgh School of Medicine, 300 Halket Street, Pittsburgh, PA 15213, USA
Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine, Texas Children’s Hospital – Pavilion for Women, 6651 Main Street, Suite F1020, Houston, TX 77030-3498, USA
Baylor College of Medicine, 1 Baylor Plaza, BCM 610, Houston, TX 77030-3498, USA
Timothy P. Canavan (Corresponding author)
Joan M. Mastrobattista
UltrasoundPregnancy failureFirst trimesterYolk sacMissed abortionThreatened abortionMiscarriageAnembryonicFetal demiseSubchorionic hemorrhage
Ultrasound imaging introduced almost four decades ago opened up a visual window for pregnancy inspection. With the advent of higher-frequency intravaginal probes, sonologists were able to study the progression of first-trimester pregnancies in great detail. Markers of successful pregnancy as well as signs of pregnancy failure were defined. In this chapter, current medical evidence behind imaging and diagnosis of first-trimester pregnancy failure are reviewed. We emphasize that no single finding can substitute for clinical judgment when examining and interpreting available data. Most pregnancy failures present with more than a single sonographic or biochemical finding.
· First-trimester pregnancy failure (pregnancy failure): lack of sonographic evidence of present or expected viability
· Threatened abortion: vaginal bleeding in a viable pregnancy up to 20 weeks gestation in the presence of a long, closed cervix
· Completed abortion: complete passage of the embryo, amnion, and chorion
· “Missed abortion”: is terminology not currently recommended since it does not adequately describe the pathophysiologic events 
· Anembryonic pregnancy: an abnormal pregnancy composed of a gestational sac without evidence of an embryo when one is expected
· Embryonic demise: presence of an embryo without cardiac activity when cardiac activity is expected
Risk Factors for Failure
Numerous risk factors are associated with first-trimester pregnancy loss; however, 40–50 % of losses are unexplained. Medical risk factors for pregnancy loss are listed in Table 15.1. Clinical factors associated with an increased risk for pregnancy failure include: increased age at first menses, lower beta human chorionic gonadotropin (β-hCG) levels, lower progesterone levels, and vaginal bleeding [2–4]. Demographic characteristics that have been linked to pregnancy failure include advanced maternal age, cigarette smoking, and a history of pregnancy loss. Stern and associates prospectively followed 83 pregnancies from 4 to 12 weeks of gestation and found that women with at least two prior spontaneous abortions were almost four times more likely to have a pregnancy failure after documentation of cardiac activity at 6 weeks compared to subjects without a history of recurrent pregnancy loss .
Medical risk factors for first-trimester pregnancy failure
Parental chromosomal abnormality
Heritable and/or acquired thrombophilias
Uncontrolled diabetes mellitus
Septated congenital uterine anomaly
Polycystic ovarian syndrome
Chemical Evidence of Pregnancy Failure
There is very little evidence to support biochemical screening for pregnancy viability. Studies evaluating pregnancy-associated plasma protein A (PAPP-A), estriol, α-fetoprotein, and inhibin A did not find statistical association with a change in these markers and early pregnancy loss. However, β-hCG and progesterone levels may have a direct relationship with early pregnancy maturation. Several studies have reported a mathematical relationship between rising β-hCG levels and “normal” pregnancy maturation. Kadar and associates reported that a 66 % rise in the β-hCG level in 48 h is associated with a normal intrauterine pregnancy . However, significant weaknesses are noted in the study sample size and methodology rendering this conclusion unreliable. The study was based on only 20 patients who were sampled inconsistently at 1- to 5-day intervals, and the 48-h interval was determined after lowering the confidence interval to 85 %. A more recent study by Barnhart and associates found β-hCG increased by 24 % in 1 day and 53 % by 2 days; however, their sampling interval was also inconsistent, varying between 1 and 7 days, raising concerns about the reproducibility of their results . Although the trend of a rising β-hCG titer may not reliably predict a viable pregnancy, a low β-hCG titer with an “empty” gestational sac should raise concern for pregnancy failure . Low progesterone levels have also been associated with an increased risk for pregnancy failure [3, 9] This association increases significantly as progesterone levels fall below 30 nmol/L . The association of pregnancy failure is strongest when correlating a woman’s age and gestational sac size. Failure increases with advancing maternal age and increased sac size .
Multiple studies have attempted to determine a level of β-hCG at which a normal intrauterine pregnancy should be identified on ultrasound, frequently referred to as the discriminatory level. By transvaginal ultrasound (TVS), this discriminatory level was determined to be 1000 mIU/mL by some authors to 2000 mIU/mL by others . This discriminatory level is defined as the threshold between an abnormal (spontaneous abortion or ectopic) and a normal intrauterine pregnancy. Doubilet and Benson reported the highest β-hCG that proceeded visualization of an intrauterine pregnancy by TVS and an eventual term live newborn as 4336 mIU/mL. They concluded that the β-hCG discriminatory level should not be used solely to determine first-trimester pregnancy management . Therefore, a β-hCG discriminatory level is not a reliable marker for predicting pregnancy failure or an abnormal pregnancy.
Ultrasound Characteristics of Early Pregnancy
Events in early pregnancy follow a predictable sequence as documented by transvaginal sonography (see Chap. 7 for details). A gestational sac is the first identifiable sonographic sign of pregnancy at approximately 5 weeks from the last menstrual period. The gestational sac is a small cystic structure, eccentrically located within the uterine cavity as a result of implantation within the endometrial lining. The sac is circular and well defined without any visible contents. By 5 weeks, 3 days, a yolk sac can be visualized as a round structure, usually eccentrically located. An embryo is first noted adjacent to the yolk sac around 6 weeks gestation. At this point, a fetal heart rate may be visualized. The embryo continues to increase in size and slowly takes on a more fetal form as it approaches 10 weeks of gestation with the crown-rump length increasing approximately 1 mm/day.
Imaging of the Early Pregnancy
The appearance and location of a first-trimester pregnancy are best imaged using a high-frequency transvaginal probe. With the transvaginal approach, the ultrasound probe is in close proximity to the pregnancy, allowing for excellent resolution. High-resolution imaging provides the necessary detail to visualize an early yolk sac, visualize and measure cardiac activity, and obtain an accurate crown-rump length measurement at an early gestational age. A transvaginal exam does not require a full bladder and in addition allows for an assessment of the adnexa and ovaries.
Ultrasound Evidence of Pregnancy Failure
The location and appearance of the gestational sac provide vital clues as to the likelihood of pregnancy failure. On initial sonographic evaluation, the location of the gestational sac is important to document and helps determine future viability and risk for pregnancy loss, as well as maternal morbidity, specifically from obstetrical hemorrhage if ectopic. The relationship of the sac to the cornual regions and to the cervix or prior uterine scar should be documented.
Gestational sacs located in the extremes (cornua or cervix) of the uterine cavity will tend to be abnormal and either fail or need to be removed due to their risk for rupture and hemorrhage. Implantation in the cornual regions requires close observation with serial examinations. Those on the cavity side of the tubal ostia, referred to as subcornual, will tend to grow into the uterine cavity and proceed normally (Fig. 15.1a, b). Those within the interstitial portion of the tube will be cornual ectopic pregnancies and need additional therapy (Fig. 15.2). Implantations close to or in the endocervical canal tend to fail due to the poor vascular infrastructure; however, some will persist, becoming cervical ectopic pregnancies (Fig. 15.3). Cervical ectopic pregnancies will eventually rupture and/or hemorrhage risking significant maternal morbidity. Identification of the gestational sac low within the uterine cavity is associated with an increased risk for failure. Nyberg and coworkers assessed gestational sac location. They reported that when a gestational sac is located within the lower uterine segment, the risk for pregnancy failure is increased with a sensitivity and positive predictive value (PPV) of 20 and 94 % .
(a) Subcorneal implantation. A transvaginal, axial, fundal image of a subcorneal implantation of a 5 week 0 day gestational sac is depicted. (b) Subcorneal implantation. In this 3D-rendered transverse image of the same pregnancy depicted in (a), the subcorneal implantation is identified by the arrow
Ectopic pregnancy. A corneal ectopic pregnancy (arrow) at 6 week 3 day is shown in this transverse image of the right uterine cornea
Cervical ectopic pregnancy. A 7 week 6 day cervical ectopic pregnancy is depicted by the arrow in this midsagittal view of the cervix
The first sign of pregnancy identified by ultrasound is the gestational sac which is a round, anechoic cystic structure with an echogenic wall eccentrically located within the endometrial lining (Fig. 15.4a). The sac is usually identified when it reaches 2–3 mm in size in the fourth week of gestation. Gestational sac size is reported as a mean sac diameter (an average of the sagittal, transverse, and anteroposterior diameters of the sac). The appearance and size of the sac are important sonographic predictors of early pregnancy failure.
Early gestational sacs. (a) A normal 4 week 1 day gestational sac is shown in the longitudinal and axial transvaginal images. Note the “donut”-shaped ring around the gestational sac known as a double decidual sac sign. (b) Transvaginal, midsagittal image of a pregnancy pseudosac within the uterine cavity is depicted with an ectopic pregnancy (not shown) at 5 weeks 2 days gestation. (c) Longitudinal and transverse images of an abnormal “tear drop”-shaped gestational sac with an abnormal-appearing yolk sac at 5 weeks 5 days gestation
A centrally located cystic structure with a thin wall usually represents pseudogestational sac, a fluid collection within the uterine cavity, rather than a gestational sac (Fig. 15.4b). A pseudogestational sac can be seen when the pregnancy is located outside of the uterine cavity as with a tubal or cervical ectopic pregnancy. It tends to be “tear drop”-shaped and lacks the expected echogenic rim of a gestational sac and may contain debris. If a pseudogestational sac is suspected, further imaging is necessary to identify a possible ectopic pregnancy.
Although there is little research to predict outcome, gestational sacs that appear collapsed or contain a significant amount of debris are at high risk for pregnancy failure (Fig. 15.4c). These pregnancies may be anembryonic or may represent a recent embryonic demise. The debris may be the result of a recent hemorrhage. Careful examination of the sac for evidence of a yolk sac and/or embryo is required since the debris may mask these structures.
Nyberg and associates analyzed the appearance of the gestational sac in 168 subjects and found that a thin decidual reaction (≤2 mm), a weakly echogenic decidual reaction, and an irregular sac contour had a PPV for pregnancy failure of 96 %, 98 % and 97 %, respectively . Moreover, the authors’ report that a gestational sac located in the lower uterine segment has a PPV of 94 % for pregnancy failure (Fig. 15.5). A distorted gestational sac shape had the highest PPV for pregnancy failure at 100 %. Although the PPV was high, the sensitivity of these findings was low, ranging from 10 % for a distorted shape to 53 % for a weak echogenic decidual reaction (Fig. 15.6).
Abnormally positioned gestational sac. This is a midsagittal, transabdominal image of a 5 week 0 day gestational sac implanted in the lower uterine segment portion (solid black arrow) of the uterine cavity with an intrauterine contraceptive device in the endocervical canal (white arrow)
Irregular gestational sac. A transvaginal, axial image is shown depicting an irregular 7 week 5 day gestational sac in a failed pregnancy found to be triploidy by karyotype. Note the cystic (hydropic) placenta (arrow) sometimes seen in triploidy
Several investigators have noted that the early gestational sac forms a cystic echogenic complex which expands into the uterine cavity and is outlined by the echogenic decidual tissue. This sonographic appearance has been referred to as the double decidual sac sign (DDS), and studies have advocated the absence of this sign as a predictor of pregnancy failure (see Fig. 15.4a). Nyberg and associates found that the absence of the DDS has a PPV of pregnancy failure of 94 %. Bradley and colleagues reported the utility of the DDS in differentiating an ectopic pregnancy from an early intrauterine pregnancy but found that the DDS was a poor predictor for pregnancy failure [11, 12]. Doubilet and Benson describe poor interobserver agreement for the presence of a DDS (κ = 0.24) and note that first-trimester outcome was unrelated to the presence of a DDS .
Yeh and associates described another early sonographic sign of pregnancy. They reported that the early gestational sac is implanted within thickened decidua on one side of the uterine cavity, and the combination of these sonographic findings was coined the intradecidual sign (IDS)  (Fig. 15.7). The IDS was identified in 92 % of intrauterine pregnancies as early as 25 days of gestation, yielding a sensitivity and specificity of 92 and 100 %. Laing and associates found the IDS to have a sensitivity and specificity of 34–66 % and 55–73 %, respectively, with poor interobserver agreement . The overall accuracy for predicting an intrauterine pregnancy was only 45 %. Chaing and colleagues revisited the utility of an IDS for determination of an intrauterine pregnancy and found more favorable sensitivity, specificity, accuracy, and interobserver agreement (kappa statistic) of 70 %, 100 %, 75 %, and 0.79, respectively . Doubilet and Benson also investigated the IDS as a sign of a viable intrauterine pregnancy and found poor interobserver agreement with a kappa statistic of 0.23. They found no statistically significant relationship between the presence of an IDS and viability at the end of the first trimester . Based on the present literature, the DDS and IDS are often not visualized or are difficult to discern, and the ultimate pregnancy outcome seems unrelated to the presence of these two findings. Given the poor agreement among investigators, these signs do not appear predictive of pregnancy success or failure.
Intradecidual sign. A transvaginal, axial image of a 5 week 1 day gestational sac with an intradecidual sign (arrow) is shown
The most predictive criterion for identifying a failed pregnancy is the presence of a large gestational sac for expected age that does not contain an embryo. Several studies have investigated a critical value for the minimal mean sac diameter above which a normal embryo should reliably be identified by TVS. Initial studies suggested a cutoff of 16 mm but were based on small numbers . Other studies identified empty gestational sacs with a mean sac diameter between 17 and 21 mm that subsequently were found to be viable pregnancies [18, 19]. Pexsters and associates found the interobserver error in the measurement of the mean sac diameter to be ±19 % . Considering the results of these studies, a 21-mm mean sac diameter by one observer could be as high as 25 mm as measured by a second observer. Therefore, a mean gestational sac diameter of 25 mm, in the absence of an embryo, would be the best diagnostic cutoff for a failed pregnancy (Fig. 15.8).
Large, empty gestational sac. This is a transvaginal, axial image of an empty 7 week 5 day gestational sac with a mean sac diameter of 27 mm, indicating a failed pregnancy
A normal gestational sac grows approximately 1 mm per day during the first trimester (Fig. 15.9) . However, predicting pregnancy failure by subnormal sac growth is not reliable . Usual timing of early pregnancy events (±0.5 weeks) includes visualization of the gestational sac by 4.5 weeks, yolk sac by 5.5 weeks and an embryo with cardiac activity by 6 weeks, but variation exists. A single examination at 6 weeks that does not demonstrate an embryo with cardiac activity is not diagnostic of pregnancy failure especially if the pregnancy is dated by the menstrual cycle, which is frequently unreliable. A second examination is recommended to confirm pregnancy failure. Once a gestational sac is visualized within the uterus, an embryo with cardiac activity should be identified sonographically within 14 days. If a gestational sac and yolk sac are visualized, an embryo with cardiac activity should be seen within 11 days [23, 24]. Failure to meet these milestones would be suggestive of pregnancy failure.
Graph depicts the mean gestational sac diameter in mm ± 2 standard deviations compared to the gestational age in weeks created with data from ref. 
The amniotic cavity is a space between the cytotrophoblast and the embryonic disc, which is lined by amnion cells. The amnion is usually visualized near the same time as the embryo (approximately 6.5 weeks). During the early first trimester (6.5–10 weeks), the diameter of the amniotic cavity is approximately equal to the embryonic crown-rump length (amniotic diameter = 1.1 × CRL − 0.07) . A small or non-visualized embryo in a well-formed amniotic cavity is suggestive of a failed pregnancy. Horrow found that a CRL/amniotic cavity difference greater than 0.48 cm (0.86 ± 0.38 cm) was associated with pregnancy failure. McKenna and associates reported that an “empty amnion” (defined as a visible amnion without an embryo) was always associated with pregnancy failure (Fig. 15.10) . Yegul and colleagues described that a visible amnion with an identifiable embryo (less than 5.4 mm) without cardiac activity was associated with pregnancy failure. This finding was referred to as the “expanded amnion sign,” and in their analysis, this sign had a PPV of 100 % . A further study by this group found that visualization of an amniotic cavity without evidence of an embryo (referred to as the “empty amnion sign”), confirmed pregnancy failure regardless of the gestational sac size with a PPV of 100 % .
Empty amnion. An empty amnion at 6 weeks 6 days gestation is shown (arrows) in this transvaginal, axial view of the uterus
The chorion is formed from mesoderm and trophoblasts and becomes the wall of the chorionic cavity. The chorionic cavity is the anechoic fluid collection in which the embryo, amnion and yolk sac are suspended and grow, and is measured as the “gestational sac.” The cavity is eventually obliterated by the expanding amnion, resulting in the single amniotic cavity.
The most significant concern for the chorion is hematoma formation. Bleeding during the first trimester of pregnancy is one of the most common obstetrical complications, occurring in approximately 14 % of all pregnancies . This bleeding can result in hematoma formation of the subchorion. Multiple studies have linked subchorionic hematomas (SCH) with both early and late adverse pregnancy outcomes. The definition of a hematoma is not always clearly defined, but the majority of investigators recognize a hematoma as a crescent-shaped, hypoechoic fluid collection behind the fetal membranes and/or the placenta. Hematomas may be subchorionic (between the chorion and myometrium) or retroplacental (behind the placenta) and frequently become filled with debris as they age [30, 31] (Fig. 15.11a, b).
(a) Subchorionic hematoma. A large subchorionic hematoma is denoted by calipers in this transvaginal, axial image at 5 weeks 5 days gestation, showing an early embryonic pole (arrow). (b) Subchorionic hematoma. This transvaginal, axial image shows a subchorionic hematoma (thick white arrow) in a 5 week 0 day gestation with a normal-appearing yolk sac (thin black arrow)
Falco and associates followed 270 pregnant women with vaginal bleeding between 5 and 12 weeks gestation and found that 17 % developed SCHs. Pregnancy failure ranged from 6 to 84 %, depending on the presence of other factors such as the gestational sac CRL difference, menstrual sonographic age difference and the embryonic heart rate . They found that the fetal heart rate was the most powerful predictor of pregnancy outcome in their linear regression model, with a low heart rate (less than 1.2 SDs which is 94 beats per minute (bpm) at 6 weeks gestation to 124 bpm at 10 weeks gestation) increasing the risk for pregnancy failure. Borlum et al. followed 380 women with vaginal bleeding and found an 11.3 % increased pregnancy loss rate in the presence of a SCH . Schauberger and colleagues found that 14 % of women with a confirmed viable pregnancy by ultrasound performed for vaginal bleeding experienced pregnancy failure by 20 weeks gestation . Additional studies on women with first-trimester vaginal bleeding have reported similar results of both early pregnancy failure and pregnancy loss up to 20 weeks gestation .
Multiple studies have investigated the risk of pregnancy loss after the identification of a SCH and the findings are mixed. Additionally, there is crossover between women with first-trimester vaginal bleeding and those in which hematoma formation is actually confirmed by ultrasound. Comparison of these studies is limited by the varied methodologies and study design limitations (small sample size, lack of a control group, limited description and analysis of patient characteristics and publication bias) [35, 36]. The rate of SCH ranged from 0.5 to 20 % in these studies, and while studies by Pedersen et al. and Stabile et al. found no association of SCH to pregnancy failure, other studies by Borlum et al. and Maso et al. found at least a twofold increased risk [32, 34, 37, 38]. Most studies did not find any statistical relationship between the hematoma volume and adverse outcome; however, Maso et al. found that the overall risk for spontaneous abortion was 2.4 times higher when the hematoma was identified before 9 weeks of gestation . One of the largest studies by Ball and coworkers evaluated 238 subjects with a SCH and found a 2.8-fold increased risk of spontaneous abortion (a loss before 20 weeks gestation) . In those subjects with a SCH, vaginal bleeding increased the risk of spontaneous abortion compared to subjects without vaginal bleeding but findings did not reach statistical significance (p = 0.057) . A systematic review and meta-analysis by Tuuli and coworkers calculated a 2.2-fold increased risk of spontaneous abortion in the presence of a SCH . Based on these findings, it is reasonable to assume that a SCH is associated with a twofold increased risk for pregnancy failure.
Harris and colleagues studied the association of a round avascular mass extending from the choriodecidual surface into the gestational sac described as a chorionic bump, with first-trimester pregnancy outcome  (Fig. 15.12a, b). They hypothesized that chorionic bumps represent choriodecidual hemorrhages and reported that the chorionic bump was associated with a fourfold increased risk for pregnancy loss, mostly in the first trimester. Sana et al. performed a retrospective case-controlled trial and found that a chorionic bump identified in the first trimester had approximately double the risk of pregnancy loss compared to matched controls. Neither study found a statistically significant relationship between the size or location of the chorionic bump and the risk of pregnancy loss .
(a) Chorionic bump. A chorionic bump (arrow) is visualized in the right longitudinal image of this 8 week 0 day gestational sac with an embryonic pole. (b) Chorionic bump. A chorionic bump (arrows) is measured in these transvaginal, axial and longitudinal images of a 5 week 0 day gestational sac
Once a gestational sac is visualized, uteroplacental circulation can be identified in most viable pregnancies (Fig. 15.13). Moving echoes within the 8- to 11-week placenta detected by grey scale imaging is noted more frequently in those with pregnancy failure compared to viable pregnancies (88–100 % vs. 36–60 %, p < 0.01–0.001) . In women with pregnancy failure, the placenta tends to have a mottled appearance due to numerous centrally located venous lakes (Fig. 15.14). Wherry and colleagues found that low-resistance arterial endometrial blood flow is associated with trophoblastic tissue but could not discriminate between a viable pregnancy and pregnancy failure . Jaffe et al. prospectively followed color Doppler interrogation of the decidual spiral arteries and the intervillous space in 100 women at 7–12 weeks gestation and recorded pregnancy outcomes . Thirteen women had pregnancy failure in the first trimester and six had second trimester medical complications including hypertension, preeclampsia and diabetes. Abnormal color Doppler imaging was defined as active blood flow in the intervillous space and a resistive index > 0.55 in the spiral arteries. A reassessment of their data targeting first-trimester failure yielded a sensitivity, specificity, PPV, and negative predictive value of 92 %, 82 %, 43 %, and 99 %, respectively. These findings suggest that color Doppler may be helpful in predicting pregnancy failure but should not be used alone as diagnostic.
Intervillous vascular flow. Color Doppler highlights the intervillous vascular flow (arrow) in this 5 week 6 day failed pregnancy
Peritrophoblastic vascular flow. This image shows normal peritrophoblastic flow (arrow) in a 4 week 6 day pregnancy
The primary yolk sac regresses by week 2 or 3 of pregnancy and is no longer visible by ultrasound. The secondary yolk sac (YS) is the earliest embryonic landmark visualized by ultrasound; it is usually identified by about the 5.5 weeks when the gestational sac is about 8–10 mm (Fig. 15.15). However, in occasional normal pregnancies, the YS may not be visualized until a gestational sac size of 20 mm . The yolk sac is a circular structure with a hyperechoic wall and measures approximately 3–5 mm. It increases in size steadily up to 8–11 weeks gestation and disappears by 12 weeks (Fig. 15.16). Identification of the YS confirms that an intrauterine fluid collection is a gestational sac even before the appearance of the embryo. Since the YS is continuous with the embryo, amnion, and connecting stalk in the early first trimester, it will typically be found close to the wall of the gestational sac.
Normal gestational sac and yolk sac. A normal 5 week 6 day gestational sac and yolk sac are shown in this parasagittal, transvaginal image
Graph compares a normal yolk sac size in mm ± 2 standard deviations with the crown-rump length in mm using data from ref. . Reprinted with permission from Lindsay DJ, Lovett IS, Lyons EA, et al. Yolk sac diameter and shape at endovaginal US: predictors of pregnancy outcome in the first trimester. Radiology 1992; 183: 115–118
The description of an abnormal or deformed YS varies slightly by study, but the majority of investigators describe an abnormal YS as having any of the following: an irregular (non-circular) shape, wrinkled margins, indented walls, collapsed walls, thick echogenic walls, doubled (appearance of 2 or more YS) or containing echogenic spots or bands (see Figs. 15.4c, and 15.17a, b). An echogenic YS, with an echogenic central portion rather than anechoic has not been considered abnormal. Only one study described adverse outcomes in pregnancies with an echogenic YS, but several others report this finding in normal pregnancies . Echogenic yolk sacs should be differentiated from a calcified YS in which acoustic shadowing is demonstrated. Calcified yolk sacs are usually indicative of a loss of fetal cardiac activity before 12 weeks of gestation .
(a) Large yolk sac. A large yolk sac (thick arrow) is seen compressing an empty amnion (thin arrow) at 6 weeks 1 day gestation in this transvaginal, midsagittal image. (b) Large yolk sac. A large yolk sac is visualized, filling the chorionic cavity in this axial, transvaginal image of a 4 week 1 day gestation
Studies have been mixed on the risk of pregnancy loss associated with abnormal-appearing YS. Lindsay and Cho and their associates both found an increased risk of pregnancy loss with abnormal-appearing YSs, but both studies followed only a small number of affected pregnancies (7 and 5, respectively) [46, 47]. Kucuk et al. followed 19 women with an abnormal-appearing YS and found increased pregnancy loss with a sensitivity and PPV of 29 % and 47 % . More recently, Tan and colleagues followed 31 women with abnormal-appearing YSs and found no statistical association with pregnancy failure . In many studies that identified abnormal-appearing YS, an embryo with cardiac activity continued normally to term. This raises concern that an abnormal YS is not consistently associated with pregnancy failure [44, 46, 49]. Therefore, an abnormal YS is, at best, a weak predictor of pregnancy failure.
An absent YS in the presence of an embryo has been associated with pregnancy loss in multiple studies [46, 47]. An increased risk of pregnancy loss has also been reported in pregnancies with an enlarged yolk sac, but in many of these studies, normal pregnancies resulted despite an enlarged YS (Fig. 15.17a, b). Berdahl et al. followed 80 women with a YS diameter ≥5 mm and found a threefold increased risk of pregnancy loss compared to those with normal-sized yolk sacs . Lindsay et al. found that an enlarged YS (greater than 2 standard deviations based on the gestational sac size) has a sensitivity and PPV for pregnancy loss of 15.6 % and 60.0 %, respectively . Chama and coworkers found that a YS diameter more or less than 2 standard deviations from the mean, predicted pregnancy failure with a sensitivity, specificity, and PPV of 91.4 %, 66.0 %, and 88.8 %, respectively . Lindsay et al. identified an association of a small YS (less than 2 standard deviations based on the gestational sac size) with pregnancy loss, giving a sensitivity and PPV of 15.6 % and 44.4 %, respectively . However, a large yolk sac when identified with a viable embryo can exist in a normal pregnancy . Based on these studies, a YS diameter greater than 2 standard deviations from the mean, in the absence of an embryo, would suggest pregnancy failure.
The presence of a YS within a gestational sac is reassuring; however, in the absence of an embryo, future viability is uncertain. Abdallah and associates followed 1060 pregnancies prospectively for viability. In the subgroup of pregnancies with a YS but without an embryo, the false-positive rate (FPR) to diagnose pregnancy failure was 2.6 % at a gestational sac diameter of 16 mm and 0.4 % at a cutoff of 20 mm, with no false positives when the gestational sac was ≥21 mm. Given the interobserver error, a cutoff of ≥25 mm was recommended to diagnose pregnancy failure when a YS is seen without an embryo .
Observation of the location, appearance and activity of the embryo can provide clues to inevitable pregnancy failure. Abnormalities of embryonic size and growth have been closely linked with pregnancy failure.
Embryonic motion can be visualized early in gestation by TVS and tends to be rapid jerking motions due to immaturity of the embryonic nervous system . Goldstein et al. reported identification of embryonic body movements starting at 8 weeks gestation, with a sensitivity and PPV of 100 and 94.3 % .
The embryo is first identified sonographically as a thickening along the YS. As the embryo grows, it assumes a C-shape and it begins to distance itself from the yolk sac, usually at around 55 days of gestation. The yolk sac maintains a thin connection to the embryo through the yolk stalk which can occasionally be visualized on TVS. The yolk stalk detaches from the midgut loop at the end of the sixth week of gestation (CRL of 8 mm) allowing the yolk sac to separate from the embryo. This separation continues until approximately the 10th–12th week of gestation when the YS begins to solidify and assumes a position between the amnion and chorion . A loss of these anatomic relationships raises concern for potential pregnancy failure.
Filly and associates, in a retrospective review of the yolk stalk in embryos of 5 mm or less without cardiac activity, reported that premature separation of the embryo from the YS (evidence that the yolk stalk had developed—the “yolk stalk sign”) was suggestive of an embryonic demise with a PPV of 100 % . They theorized that visualization of the yolk stalk is not expected until a CRL of 8 mm when cardiac activity is expected. Hence, the lack of cardiac activity is further evidence of embryonic demise.
The embryo has a classic appearance as it grows from a thickening along the YS into a fetus with recognizable head and limbs. Initial visualization of the embryo on TVS occurs when it reaches 2–3 mm in size and has the appearance of a straight echogenicity along the YS wall. At about day 21, the embryo develops a C-shape as the caudal neuropore elongates. At 24 days, a heart bulge can be seen, and by day 28, the embryo is 4 mm in length and limb buds appear. Distinct limbs may be visualized at about day 35 when the embryo measures 8 mm. A visible crown-rump length is not identified until about 49 days with the embryo measuring 18 mm (Fig. 15.18) .
Normal orientation of yolk sac, embryo and amnion. This transvaginal, axial image of the normal orientation of the yolk sac (YS), embryonic pole (CRL) and amnion are depicted
There is no rigorous research assessing pregnancy outcomes in the absence of the above landmarks, but they may provide guidance clinically. A straight-appearing 4-mm embryo should raise concern for possible pregnancy failure, especially in the absence of cardiac activity prompting a follow-up exam. TVS has the potential to image the shape of the embryo, and this information can be used with other findings. Further study is ongoing, especially in the use of three-dimensional imaging, to evaluate the embryonic appearance and assess risk for pregnancy failure.
Multiple investigators have assessed embryo size compared to menstrual age in normal pregnancies and from this developed nomograms and regression formulas for embryonic growth. On average, these studies have supported a normal embryo growth rate of approximately 1 mm/day  (Fig. 15.19). A study by Bottomly et al. assessed embryonic growth and concluded that embryo growth is not linear, and their study questioned the reliability of an absolute growth rate for determining fetal viability . Reljic found that when the CRL was greater than 2 standard deviations below the mean for expected gestational age, and ≤18 mm, there was a 6.5-fold increased risk of pregnancy failure compared to those at or above the mean. The risk of pregnancy failure increased as the discrepancy increased . Reljic did not find a similar association when the CRL was >18 mm. A study by Stern and associates evaluating pregnancy failure after documentation of an embryonic heart rate (EHR) found that sonographic gestational age by CRL lagged by more than 0.6 weeks behind menstrual dates in 86 % of women studied . Mukri et al. prospectively monitored the embryo/fetal growth in 292 pregnant women and found that there was a statistically significant difference between the gestational age by CRL compared to expected gestational age by LMP in pregnancies that ended in a demise by 11–14 weeks . Sixty-one percent of the pregnancies that failed had CRLs that were more than 2 standard deviations below the mean; there was a direct relationship between an increasing discrepancy and the risk of pregnancy failure. At a threshold of 2 standard deviations below the mean, the sensitivity and PPV for pregnancy loss were 61 % and 31 %.
The expected crown-rump length (CRL) in cm ± 2 standard deviation is compared to the menstrual age in weeks in this graph created with data from ref. 
Numerous investigators have extensively evaluated a threshold CRL to definitively confirm an embryonic demise in the absence of cardiac activity. It is critically important to apply a threshold that provides accuracy and reliable reassurance to patients and takes into account interobserver error. Abdullah and associates in a prospective study evaluating CRL measurements in the absence of cardiac activity, determined false-positive rates in diagnosing pregnancy failure as 8.3 % using a CRL of 4.0 or 5.0 mm with no false positives found when using a CRL of ≥5.3 mm . Accounting for inter- and intra-observer variation, a threshold CRL of ≥7 mm is recommended to diagnose pregnancy failure, when cardiac activity is not visualized.
Anatomic structural anomalies are now detected in the first trimester with increasing frequency (also see Chap. 19). An anomaly does not necessary predicate a pregnancy failure, but certain anatomic abnormalities may be associated with aneuploidy, which increases the risk of pregnancy failure. The sonologist should exercise caution, as there are developmental changes in the embryonic and early fetal periods that can be misinterpreted as anomalies (Figs. 15.20, 15.21, and 15.22). Table 15.2 lists some of the common first-trimester ultrasound pitfalls. Anomalies visualized in the first trimester are listed in Table 15.3 (Figs. 15.23, 15.24, 15.25, 15.26, and 15.27).
Physiologic gut herniation. A physiologic herniation of fetal bowel (thin arrow) into the umbilical cord (thick arrow) is visualized in this transvaginal, midsagittal image of a 10 week 0 day fetus. This herniation was not seen at a 14 week follow-up exam
Embryonic heart bump. The embryonic heart is noted as a “bump” (see arrow) in the mid torso of this normal 8 week 5 day embryo as seen in this transvaginal, axial image
Prominent rhombencephalon. Transvaginal, axial image of a normal 9 week 3 day fetus showing a prominent rhombencephalon mistaken for possible hydrocephalus. An 18-week fetal anatomy survey revealed normal intracranial anatomy
Developmental pitfalls on first-trimester ultrasound
Normal embryonic development
Cystic space in the posterior cranium
Dandy walker malformation, hydrocephalus
Mass at the fetal umbilical cord insertion
Physiologic herniation of the fetal bowel
Embryonic heart seen as a mass on the chest
In the early embryo the heart is normally an anterior chest bump
Anomalies identified on first-trimester ultrasound
Bladder outlet obstruction
Limb-body wall defect Omphalocele/abdominal wall defect
Omphalocele. An omphalocele (thick arrow) is noted with a thickened nuchal translucency (thin arrow) in this transvaginal, axial image of an 11 week 4 day fetus
Conjoined twins. The thin arrow depicts Fetus A and the thick arrow Fetus B in this transvaginal, midsagittal image of omphalopagus conjoined twins at 11 weeks 0 days gestation
Thoracoabdominal wall defect. Transvaginal, axial image of an 11 week fetus showing a defect in the thoracoabdominal wall (thick arrow) with the heart and bowel contents herniating from the fetus. A thickened nuchal translucency (thin arrow) is also noted
(a) Fetal anasarca. This transvaginal, axial image shows an 11 week 6 day fetal demise (calipers) with anasarca found to be triploidy by karyotype. (b) Fetal anasarca. A 13 week 6 day fetal demise with anasarca (arrows) is visualized in this transvaginal, longitudinal image also showing a thickened nuchal translucency. A karyotype of the products of conception revealed trisomy 13
Large amnion with abnormal-appearing fetus. A 9 week 4 day abnormal-appearing fetus with an enlarged amnion (arrows) is visualized by transvaginal imaging in the axial plane. Cardiac activity is not visualized when cardiac activity was previously demonstrated. The fetal karyotype was 45X
Embryonic Heart Rate
The EHR increases with gestational age, ranging from 90 to 113 bpm at 6 weeks gestation to a plateau of 140–170 bpm at about 9 weeks gestation . Figure 15.28 depicts the mean EHR with +/−2 standard deviations plotted against the crown-rump length for normal pregnancies [59, 60].
The graph shows the comparison of the embryonic heart rate in bpm ± 2 standard deviations to the crown-rump length in mm created with data from refs.  and 
Multiple studies have determined that a low EHR, less than 85–100 bpm at a gestational age below 8 weeks gestation, is associated with pregnancy loss [58, 61–63]. The largest prospective study by Stefos and associates evaluated 2164 women and identified a threshold EHR of 85 bpm for predicting pregnancy loss at less than 6 weeks 3 days gestation. The threshold increased to 125 bpm between 7 weeks 4 days and 8 weeks 0 days . With increasing gestational age, studies report an increase in the threshold EHR. Of note, the risk for pregnancy loss increases as the EHR decreases, especially between 6 and 9 weeks gestation [61, 64, 65]. A slow EHR (<90 bpm) when observed at 6–7 weeks gestation, carries a risk of first-trimester pregnancy loss of about 25 % in several studies even in cases where the EHR is in the normal range at an 8-week follow-up exam [64, 65]. An increased EHR (greater than 2 standard deviations above the mean) has not been associated with pregnancy loss .
Aneuploidy has been linked to abnormal fetal heart rates (FHR) [66–68]. Liao and associates retrospectively evaluated 25,000 women who underwent first-trimester screening and found that fetuses with trisomy 21, trisomy 13 and Turner syndrome had an increased probability of a FHR greater than 2 standard deviations above the mean (9.7 %, 67.4 % and 52.2 %, respectively), while fetuses with trisomy 18 and triploidy had an increased probability of a decreased FHR more than 2 standard deviations below the mean (18.7 % and 30.0 %, respectively) .
Retained Products of Conception
Retained products of conception (RPOC) are the persistence of placental and/or fetal tissue in the uterus, following a miscarriage, termination of pregnancy or delivery. It complicates 1 % of pregnancies and is most common after medical termination of pregnancy and second trimester miscarriage. The most common patient complaints associated with RPOC are vaginal bleeding, pelvic pain, and/or fever. Abbasi and colleagues found that vaginal bleeding had the highest sensitivity and specificity for RPOC of 93 % and 50 %, respectively .
Clinical evaluation for RPOC is inaccurate, therefore, TVUS is frequently chosen for definitive evaluation. Sadan et al. reported that the presence of hyperechoic or hypoechoic material within the uterine cavity or an endometrial lining thicker than 8 mm had a PPV of 71 % for histologically confirmed RPOC . Durfee and associates found that an endometrial mass was the most sensitive and specific sonographic feature of RPOC (79 % and 89 %, respectively), with a PPV of 59 %  (Fig. 15.29). An endometrium lining greater than 10 mm, as an isolated finding, had low sensitivity and specificity and was detected more frequently in patients without RPOC. Durfee et al. also found that complex fluid alone, identified within the uterine cavity, was a poor predictor of RPOC, and the absence of sonographic findings had a NPV for RPOC of 100 % .
This is a longitudinal transvaginal image of a 39-year-old woman who presented to the emergency room complaining of vaginal bleeding and pelvic pain at 10 weeks 5 days pregnant. A previously identified gestational sac and fetus are not seen. The arrows identify echogenic masses within the uterine cavity
Color Doppler Imaging
Color Doppler mapping of the uterine cavity is advocated to further evaluate the uterine cavity for RPOC (Fig. 15.30). Durfee and associates found that blood flow in the endometrium had a PPV of 75 % for the presence of RPOC, but a NPV of 46 %. They concluded that color Doppler imaging was not helpful for predicting RPOC . Kamaya et al. graded the endometrial vascularity, in women referred for suspected RPOC, by color Doppler imaging. The endometrium was graded from type 0, no detectable vascularity, to type 3, marked vascularity . They found that detectable vascularity of any type (1–3) had a high likelihood of RPOC, with a PPV of 96 %. All women with types 2 and 3 vascularity were found to have RPOC, while type 0 vascularity did not exclude RPOC. These findings suggest that color Doppler mapping of the uterine cavity can improve the sensitivity and PPV for predicting RPOC.
A longitudinal, transvaginal, color Doppler image is depicted of the same patient described in Fig. 15.29. Vascular flow is demonstrated within the echogenic masses. The pathology from a dilatation and curettage revealed retained products of conception
Recurrent Pregnancy Loss
Recurrent pregnancy loss (RPL) is most commonly defined as two or more failed pregnancies, which have been documented by ultrasound or histopathological examination . It occurs in less than 5 % of women, with 1 % having three or more pregnancy losses. There are multiple suspected etiologies, with cytogenetic (2–5 %), antiphospholipid syndrome (8–42 %) and anatomic anomalies (1.8–37.6 %) comprising the majority of causes. Congenital uterine anomalies are present in 12.6 % of women with RPL and can be characterized by 3-D ultrasound imaging. The highest rates of RPL are present in women with congenital uterine anomalies: septate (44 %), bicornuate (36 %), and arcuate (26 %) uteri . Despite these findings, a definitive diagnosis for RPL is determined in only 50 % of women. The mechanisms of RPL are not completely understood and research is ongoing.
In the absence of a definitive etiology, treatment is very limited. However, Brigham and associates reported that despite three consecutive miscarriages, 70 % of women with idiopathic RPL conceived and 55 % went on to have fetal survival beyond 24 weeks gestation . No statistical difference in outcome between women with two and those with three previous losses was found. In addition, 78 % of miscarriages in women with recurrent losses were identified between 6 and 8 weeks gestation, and in 89 %, cardiac activity was never visualized . Cardiac activity at 8 weeks was associated with a 98 % chance of successful pregnancy that increased to 99.4 % when cardiac activity was demonstrated at 10 weeks gestation.
Ultrasound assessment of the first-trimester pregnancy has dramatically improved the diagnostic capabilities of clinicians over the past four decades. Once a hidden, mysterious part of pregnancy, the first trimester is now open to investigation and examination. Imaging the stages of embryonic and fetal development provide the clinician with valuable information which can be used to screen for aneuploidy, evaluate for anomalies and identify markers of fetal viability. The best predictors of pregnancy failure are the absence of an embryo once the mean gestational sac size reaches 25 mm and the absence of cardiac activity once the embryo is ≥7 mm. These thresholds are justifiably conservative but allow us to reassure our patients with confidence of the sonographic diagnosis of pregnancy failure.
· The β-hCG discriminatory level to visibly confirm an intrauterine pregnancy by transvaginal ultrasound is 4000 mIU/mL.
· An empty gestational sac with a mean sac diameter of ≥25 mm is considered anembryonic.
· An embryo without cardiac activity at a crown-rump length of ≥7 mm is considered an embryonic demise.
· A fetal heart rate <90 bpm at >6 weeks gestation is concerning for impending pregnancy failure.
· A gestational sac or embryo that does not grow 1 mm/day over 7–10 days is concerning for pregnancy failure.
· Absence of a viable embryo ≥2 weeks after identification of a gestational sac without a yolk sac is anembryonic.
· Absence of a viable embryo ≥11 days after identification of a gestational sac with a yolk sac is anembryonic.
· 60 % of spontaneous abortions at <12 weeks gestation are due to chromosomal abnormalities.
· The diagnosis of retained products of conception can be suspected when hyperechoic or hypoechoic material is visualized within the uterine cavity or the endometrial lining is thicker than 8–10 mm, although the positive predictive value is less than optimal. Color Doppler may be helpful in these situations.
· A definitive etiology for recurrent pregnancy loss is determined in only 50 % of women and, in the absence of a conclusive diagnosis, treatment is very limited
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