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Failed Intrauterine Pregnancy: What Is a Failed Pregnancy, What Is Not?

CANAVAN, TIMOTHY P. MD, MSc

Clinical Obstetrics and Gynecology: September 2017 - Volume 60 - Issue 3 - p 562–574
doi: 10.1097/GRF.0000000000000301
Advances in Ultrasound and Obstetrical Imaging

Pregnancy failure is defined as a lack of sonographic evidence of current or expected viability. Technologic advances in ultrasound imaging continue to redefine diagnostic criteria of pregnancy failure or success. When evaluating a pregnancy, the first step is an assessment of maternal risk factors for failure. Imaging clues such as an empty gestational sac measuring ≥25 mm or an embryo ≥7 mm without cardiac activity are reliable signs of pregnancy failure, whereas embryonic growth <1 mm/d is not. Combinations of sonographic findings can be used for a more accurate prediction of pregnancy success or failure.

Division of Ultrasound, Magee Womens Hospital, University of Pittsburgh, Pittsburgh, Pennsylvania

The author declares that there is nothing to disclose.

Correspondence: Timothy P. Canavan, MD, MSc, Division of Ultrasound, Magee Womens Hospital, University of Pittsburgh, Pittsburgh, PA. E-mail: canavant@mail.magee.edu

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Introduction

Ultrasound imaging, introduced almost 40 years ago, provides clinicians a window into embryonic growth and development. High-frequency intracavitary probes allow a unique opportunity to study first trimester pregnancies in great detail. Sonographic signs of pregnancy success and failure are defined, giving the clinician tools to better care for patients. In this chapter, current sonographic and medical evidence of first trimester pregnancy success and failure are reviewed. No single imaging clue can substitute for clinical judgment when interpreting combinations of available data. Pregnancy success and failure frequently present with more than a single sonographic or biochemical sign.

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Definitions

  • 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 describing a nonviable first trimester pregnancy that is not recommended as it does not adequately describe the pathophysiologic events.1
  • Anembryonic pregnancy: an abnormal pregnancy composed of a gestational sac (GS) without evidence of an embryo when one is expected.
  • Embryonic demise: presence of an embryo without cardiac activity when cardiac activity is expected.
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Sonographic Characteristics of Normal First Trimester 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 (YS), visualize and measure cardiac activity, and obtain an accurate crown-rump length (CRL) measurement at an early gestational age. Transvaginal sonography (TVS) does not require a full bladder and yields excellent windows for an assessment of the adnexa and ovaries.

Events in early pregnancy follow a predictable sequence of events. A GS is the first identifiable sonographic sign of pregnancy imaged as a small cystic structure, eccentrically located within the endometrial lining. By 5 weeks 3 days, a YS can be visualized as a round, fluid-filled structure located eccentrically, followed by an embryo at approximately 6 weeks of gestation.

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GS

This round, anechoic cystic structure with an echogenic wall eccentrically located within the endometrial lining as mentioned is the first sign of pregnancy identified by ultrasound (Fig. 1). The sac is usually detected when it reaches 2 to 3 mm size in the fourth week of gestation. GS size is reported as a mean sac diameter (MSD) measured as an average of the sagittal, transverse, and anteroposterior diameters of the sac.

FIGURE 1

FIGURE 1

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YS

The YS is the earliest embryonic landmark identified by ultrasound and is usually visualized by about 5.5 weeks gestation when the GS is about 8 to 10 mm. In occasional normal pregnancies, the YS may not be visualized until the GS size reaches 20 mm.2 The YS is a circular structure with a hyperechoic wall and measures approximately 3 to 5 mm. It steadily increases in size up to 8 to 11 weeks of gestation and is usually not visualized after 12 weeks. Occasionally the YS appears as 2 parallel lines which are the leading edge and posterior wall of the YS, rather than a complete circle.

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AMNION

The amniotic cavity is a space between the cytotrophoblast and the embryonic disc and is lined by amnion cells. The amnion is first visualized at about 6 weeks of gestation when the embryo is also identified. The amnion is a thin-wall cystic structure that closely approximates the early embryo (Fig. 2). It remains in close proximity and grows proportionate to the embryo from 6 to 10 weeks of gestation when the mean diameter of the amniotic cavity is approximately 10% larger than the embryo. This relationship continues until fetal urine production begins and the amniotic cavity begins to expand with fluid at approximately 10 weeks.

FIGURE 2

FIGURE 2

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EMBRYO

An embryo is first noted adjacent to the YS at approximately 6 weeks of gestation when it is about 1 to 2 mm in length. It is frequently demonstrated as a thickening along the edge of the YS. Motion of the embryo can be detected by TVS as early as 8 weeks.3 Cardiac activity should be seen once the CRL reaches 7 mm.4 The embryonic heart rate (EHR) increases with gestational age, starting at 90 to 113 bpm at 6 weeks to a peak of 140 to 170 bpm at about 9 weeks gestation.5

As the embryo grows, it develops a C-shape and starts to distance itself from the YS, usually at around 55 days of gestation. The yolk stalk detaches from the midgut loop at the end of the sixth week of gestation (CRL of 8 mm) and the YS separates from the embryo. The embryo increases arithmetically in size and slowly takes on a more fetal appearance as it approaches 10 weeks gestation. The appearance of the embryo is nondescript until 7 to 8 weeks, when the embryo begins to curl and the spine can be visualized.

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Sonographic Characteristics of Pregnancy Failure

GS

The location and appearance of the GS provides vital clues as to the likelihood of pregnancy failure. The location of the GS can be used to predict potential viability, risk for pregnancy failure, and to detect an ectopic pregnancy. The relationship of the GS to the cervix, a prior uterine scar or the uterine cornua requires accurate assessment.

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Location

GSs located in the cornua or cervix are most likely abnormal and will either fail or require surgical resection due to the risk for rupture and hemorrhage. Implantation suspected within the cornual regions requires close evaluation and serial examination. Pregnancies on the cavity side of the tubal ostia are referred to as subcornual and will tend to grow into the uterine cavity and proceed normally (Fig. 3). Pregnancies identified within the interstitial portion of the tube are cornual ectopic pregnancies necessitating additional therapy (Fig. 4). Implantations close to or within the endocervical canal usually fail due to poor vascular support; however, some will persist, becoming cervical ectopic pregnancies (Fig. 5). Cervical ectopic pregnancies will inevitably rupture yielding hemorrhage and risk for significant maternal morbidity.

FIGURE 3

FIGURE 3

FIGURE 4

FIGURE 4

FIGURE 5

FIGURE 5

Cesarean scar implantations are rising and represent a new class of ectopic gestations that may result in significant obstetrical hemorrhage. Scar ectopics often present with vaginal bleeding and have a high probability of rupture. They are differentiated from lower uterine cavity implantations by their asymmetric location within the myometrial cleft left by the previous hysterotomy and by demonstration of vascular flow from the chorion into the myometrial cleft (Figs. 6, 7).

FIGURE 6

FIGURE 6

FIGURE 7

FIGURE 7

A GS identified within the lower uterine cavity is associated with an increased risk for pregnancy failure. Nyberg et al6 assessed GS locations and demonstrated that a GS located in the lower uterine cavity had an increased risk for pregnancy failure, with a sensitivity and positive predictive value (PPV) of 20% and 94%.

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Appearance

The appearance and size of the sac are important sonographic predictors of early pregnancy success or failure. A thin walled, cystic structure visualized within the central uterine cavity is most likely a pseudogestational sac. These cystic structures tend to contain debris-filled fluid or a collection of blood and are not GSs (Fig. 8). Pseudogestational sacs are usually “tear drop” in shape and lack the expected echogenic rim of a GS and are usually associated with a pregnancy located outside of the uterine cavity such as a tubal or cervical ectopic pregnancy. If a pseudogestational sac is suspected, further imaging is recommended to evaluate for an ectopic pregnancy.

FIGURE 8

FIGURE 8

There is very little data to guide prognosis when the GS appears collapsed or contains debris. These pregnancies may be anembryonic, contain a recent embryonic demise or may be a normal variant. The debris may be the result of a recent hemorrhage. Thorough evaluation of the sac for evidence of a YS and/or embryo is required since the debris may obscure these structures.

Nyberg et al6 evaluated the appearance of the GS in 168 subjects and found that a thin (≤2 mm) or weakly echogenic decidual reaction or an irregular sac contour had a PPV for pregnancy failure of 96, 98, and 97 percentile, respectively. An irregular GS shape had the highest PPV for pregnancy failure at 100%. Although the PPVs were high, the sensitivity of these findings was low, ranging from 10% for an irregularly shaped sac to 53% for a weak echogenic decidual reaction.

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Size/Growth

The most accurate predictor for a failed pregnancy is the ultrasound finding of a large GS for expected age that does not contain an embryo. Multiple studies have assessed a critical value for the minimal MSD above which a normal embryo should reliably be identified by TVS. Early studies suggested a threshold of 16 mm but these studies were based on small numbers.4 Later studies found empty GCs with a MSD between 17 and 21 mm that developed into viable pregnancies.2,7 Pexsters et al8 determined the interobserver error in the measurement of the MSD to be ±19%. Considering the findings from these studies, a 21 mm MSD by one observer could be as high as 25 mm by a second observer. Therefore, a mean GS diameter of 25 mm, in the absence of an embryo, is the most reliable diagnostic cutoff for a failed pregnancy (Fig. 9).

FIGURE 9

FIGURE 9

A normal GS grows about 1 mm/d, but subnormal growth does not predict pregnancy failure.9 An ultrasound examination at 6 weeks gestation 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, since menstrual dating is frequently undependable. A second examination is recommended to confirm pregnancy failure. Once a GS is visualized within the uterus, an embryo with cardiac activity should be visualized by TVS by 14 days. If a GS and YS are visualized, an embryo with cardiac activity should be seen after 11 days.3 Failure to meet these milestones is consistent with pregnancy failure.

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AMNION

The amnion is visualized at about the same time as the embryo (approximately 6.5 wk). From 6.5 to 10 weeks, the diameter of the amniotic cavity is approximately equal to the embryonic CRL. Horrow demonstrated that a CRL/amniotic cavity difference >0.48 cm (0.86±0.38 cm) was associated with pregnancy failure. McKenna et al10 found that an “empty amnion” (defined as a visible amnion without an embryo) was always associated with pregnancy failure (Fig. 10). Yegul and Filly reported that a visible amnion with an identifiable embryo (<5.4 mm) without cardiac activity (referred to as the “expanded amnion sign”) was associated with pregnancy failure (PPV of 100%).11 A further study by this group demonstrated that visualization of an amniotic cavity without evidence of an embryo (referred to as the “empty amnion sign”), was associated with pregnancy failure regardless of the GS size with a PPV of 100%.12

FIGURE 10

FIGURE 10

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PLACENTA/CHORIONIC FRONDOSUM

The most common concern for the chorion is hematoma formation. Bleeding during the first trimester of pregnancy is the most common obstetrical complication, occurring in approximately 14% of all pregnancies.13 Bleeding can cause hematoma formation in the subchorion. The definition of a subchorionic hematoma (SCH) varies, but the majority of investigators describe a SCH as a crescent-shaped, hypoechoic fluid collection behind the fetal membranes and/or the placenta (Fig. 11).

FIGURE 11

FIGURE 11

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Vaginal Bleeding

Falco et al14 followed 270 women with vaginal bleeding from 5 to 12 weeks gestation and discovered that 17% developed SCHs. Pregnancy failure in these subjects ranged from 6% to 84%, depending on other factors such as the difference in the GS and CRL, the menstrual sonographic age difference and the EHR. Their linear regression analysis found that the fetal heart rate was the most significant predictor of pregnancy outcome, with a low heart rate (bradycardia), defined as <−1.2 SD from the mean (94 bpm at 6 wk gestation to 124 bpm at 10 wk gestation), increasing the risk for pregnancy failure. Borlum et al15 followed 380 women with vaginal bleeding and a living fetus >8 weeks gestation and reported an 11.3% increased risk of pregnancy loss in subjects with a SCH.

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Hematoma

Several studies have investigated the risk of pregnancy loss after the identification of a SCH with mixed results. Comparison of these studies is limited by the mixed methodologies and study design limitations (small sample size, lack of a control group, limited description of the hematoma, limited analysis of patient characteristics, and publication bias).16,17 The rate of SCH ranged from 0.5% to 20%, and while studies by Pedersen and Mantoni18 and Stabile et al20 found no association of SCH with pregnancy failure, other studies by Borlum et al15 and Maso et al19 discovered at least a 2-fold increased risk. Most studies did not demonstrate any statistical relationship between the hematoma volume and adverse outcome; however, Maso et al19 determined that the overall risk for spontaneous abortion was 2.4 times higher when the hematoma was identified before 9 weeks of gestation. The largest study by Ball et al21 evaluated 238 women with a SCH and found a 2.8-fold increased risk of spontaneous abortion before 20 weeks gestation. In women with a SCH, vaginal bleeding increased the risk of spontaneous abortion compared with subjects without vaginal bleeding but their findings did not reach statistical significance (P=0.057).21 A systematic review and meta-analysis by Tuuli et al16 reported a 2.2-fold increased risk of spontaneous abortion in the presence of a SCH. On the basis of these data, it is a reasonable estimate that a SCH is associated with a 2-fold increased risk for pregnancy failure.

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Chorionic Bump

Harris et al22 evaluated the association of a chorionic bump, defined as a round avascular mass extending from the choriodecidual surface into the GS, with first trimester pregnancy outcome (Fig. 12). They hypothesized that chorionic bumps are choriodecidual hemorrhages and found that chorionic bumps are associated with a 4-fold increased risk for pregnancy failure. Sana and colleagues performed a retrospective case-controlled trial and determined that a chorionic bump was associated with double the risk of pregnancy loss compared with matched controls. Neither study identified a statistically significant association between the size or location of the chorionic bump and the risk of pregnancy loss.23 Wax et al24 found that an isolated chorionic bump was associated with an increased risk for aneuploidy with a positive likelihood ratio of 4.1.

FIGURE 12

FIGURE 12

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YS

Identification of the YS confirms that an intrauterine fluid collection is a GS even before the appearance of the embryo. As the YS is continuous with the first trimester embryo, amnion and connecting stalk, it is typically found close to the wall of the GS.

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Appearance

The classification of an abnormal YS varies slightly by study, but most investigators describe an abnormal YS as having any of the following characteristics: an irregular (noncircular) shape, wrinkled margins, indented walls, collapsed walls, thick echogenic walls, doubled (appearance of 2 or more YS) or containing echogenic spots or bands (Fig. 13). A centrally echogenic YS has not been found to be related to adverse outcome. One study identified adverse outcomes in pregnancies with an echogenic YS, but many others have found this finding in normal pregnancies.25 Echogenic YSs need to be differentiated from calcified YSs, which demonstrate acoustic shadowing. Calcified YSs are usually associated with a loss of fetal cardiac activity (Fig. 14).26

FIGURE 13

FIGURE 13

FIGURE 14

FIGURE 14

Studies have been mixed on the association of abnormal appearing YSs with the risk of pregnancy failure. Lindsay et al27 and Cho et al28 found an increased risk of pregnancy failure with abnormal appearing YSs, but both studies followed only a small number of affected pregnancies (7 and 5, respectively). Tan et al25 monitored 31 women with abnormal appearing YSs and found no statistical association with pregnancy failure. In many studies which followed abnormal appearing YSs, an embryo with cardiac activity continued normally to term. These findings would support that abnormal YSs are not consistently associated with pregnancy failure.

An absent YS in the presence of a viable embryo has been linked with pregnancy failure in multiple studies.27,28 Enlarged YS have been associated with an increased risk of pregnancy failure, but are also found in normal pregnancies. Berdahl et al29 monitored 80 women with a YS diameter ≥5 mm and found a 3-fold increased risk of pregnancy failure. Lindsay et al27 identified that an abnormally sized YS (either >2 or <2 SD based on GS size) had a sensitivity and PPV for pregnancy loss of 16%, 60%, 16%, and 44%, respectively. Chama et al30 demonstrated that a YS diameter more or less than 2 SD from the mean predicted pregnancy loss with a sensitivity, specificity, and PPV of 91%, 66%, and 89%, respectively. On the basis of these data, a YS diameter >2 SD from the mean, in the absence of an embryo, would suggest pregnancy failure.

The presence of a YS within a GS is reassuring; however, in the absence of an embryo, future viability is uncertain. Abdallah and colleagues followed 1060 pregnancies prospectively for viability and in the subgroup of pregnancies with a YS, but without an embryo, the false-positive rate to diagnose pregnancy failure was 2.6% at a GS diameter of 16 mm and 0.4% at a cutoff of 20 mm. There were no false positives when the GS was ≥21 mm. Taking into account the interobserver error, a cutoff of ≥25 mm GS size was recommended to diagnose pregnancy failure when a YS is seen without an embryo.7

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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.

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Embryonic Motion

Embryonic motion can be visualized in the early first trimester by TVS and tends to be rapid jerking motions due to embryonic nervous system immaturity.3 Goldstein et al3 identified embryonic body movements starting at 8 weeks gestation, with a sensitivity and PPV of 100% and 94%.

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Appearance

The embryo has a characteristic appearance as it grows from a thickening along the YS into a fetus with recognizable head and limbs. Initial demonstration of the embryo on TVS occurs when it reaches 2 to 3 mm size. It 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. A visible CRL is not identified until about 49 days with the embryo measuring 18 mm.31 There is no rigorous research assessing pregnancy outcomes in the absence of the previously discussed normal developmental landmarks, but their delay or absence can provide guidance clinically. A straight appearing 4 mm embryo should raise concern for possible pregnancy failure, especially when cardiac activity is not visualized, and a follow-up exam should be considered. TVS can image the shape of the embryo, and this information can be used with other findings to determine pregnancy failure.

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Size/Growth Rate

Investigators have assessed normal embryo size compared with menstrual age and from these data nomograms and regression formulas for embryonic growth have been developed. These studies found a normal embryo growth rate of approximately 1.3 mm/d.32 A study by Bottomley et al33 evaluated embryonic growth and found that embryo growth is not linear, and their study did not support an absolute growth rate for determining fetal viability. Reljic34 determined that when the CRL was >2 SD below the mean for gestational age and ≤18 mm, there was a 6.5-fold increased risk of pregnancy failure compared with those at or above the mean and this risk increased as the discrepancy increased. However, Reljic did not show a similar association when the CRL was >18 mm. Stern and Coulam35 evaluated pregnancy failure after confirmation of embryonic cardiac activity and found that CRL gestational age lagged by more than 0.6 weeks behind menstrual gestational age in 86% of women studied. Mukri et al36 prospectively studied the embryo/fetal growth in 292 pregnant women and 61% of pregnancy failures had CRLs that were >2 SD below the mean and there was a direct relationship between an increasing discrepancy and the risk of pregnancy failure. At a threshold of 2 SD below the mean, the sensitivity and PPV for pregnancy failure were 61% and 31%, respectively.

Many investigators have studied a threshold CRL to definitively confirm an embryonic demise in the absence of cardiac activity. This threshold must provide an accurate and reliable reassurance to patients and take into account interobserver error. Abdallah et al37 performed a prospective study monitoring the CRL and embryonic cardiac activity and determined the false-positive rate for pregnancy failure was 8.3% using a CRL of 4.0 or 5.0 mm, but there were no false positives using a CRL of ≥5.3 mm. On the basis of interobserver and intraobserver error, a threshold CRL of ≥7 mm is recommended to diagnose pregnancy failure when cardiac activity is not visualized.

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Anatomy

Structural anatomic anomalies can be detected in the first trimester with increasing frequency using TVS (Figs. 15–18). An anomaly does not always result in pregnancy failure, but certain anatomic abnormalities may be associated with aneuploidy, which increases the risk for pregnancy failure. The sonologist needs to exercise caution when diagnosing anomalies in the first trimester as there are developmental changes in the embryo and early fetus which can be misinterpreted as anomalies (Figs. 19, 20).

FIGURE 15

FIGURE 15

FIGURE 16

FIGURE 16

FIGURE 17

FIGURE 17

FIGURE 18

FIGURE 18

FIGURE 19

FIGURE 19

FIGURE 20

FIGURE 20

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EHR

Several studies have determined that an EHR <85 to 100 bpm at a gestational age below 8 weeks is associated with pregnancy failure.5,38–40 A large prospective study by Stefos and colleagues evaluated 2164 women and determined a threshold EHR of 85 bpm for predicting pregnancy failure at <6 weeks 3 days gestation. This threshold is increased to 125 bpm between 7 weeks 4 days and 8 weeks 0 day.38 As gestational age increases, studies report an increase in the threshold EHR. The risk for pregnancy failure increases as the EHR decreases, most notably between 6 and 9 weeks gestation.38,41,42 An EHR <90 bpm observed at 6 to 7 weeks gestation, carries a risk of pregnancy loss of about 25% in multiple studies, even in subjects where the EHR was in the normal range at an 8-week follow-up exam.41,42 An EHR >2 SD above the mean has not been shown to increase the risk for pregnancy failure.41

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Conclusions

Sonographic assessment of the first trimester pregnancy has dramatically improved the diagnostic capabilities of clinicians over the past 4 decades. First trimester pregnancy was once a hidden, mysterious part of pregnancy, but is now open to investigation and examination by TVS. Imaging of the stages of embryonic and fetal development can provide the clinician with valuable information that can be used to screen for aneuploidy, evaluate for anomalies, and identify markers predictive of pregnancy failure. The best predictors of pregnancy failure are the absence of an embryo once the mean GS size reaches 25 mm and the absence of cardiac activity once the embryo is ≥7 mm. These thresholds are justifiably conservative but allow physicians to reassure patients with confidence of the sonographic diagnosis of pregnancy failure.

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TEACHING POINTS

  • An empty GS with a MSD of ≥25 mm is considered anembryonic.
  • An embryo without cardiac activity at a CRL 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 GS or embryo that does not grow 1 mm/d over 7 to 10 days is concerning for pregnancy failure.
  • Absence of a viable embryo ≥14 days after identification of a GS without a YS is anembryonic.
  • Absence of a viable embryo ≥11 days after identification of a GS with a YS is anembryonic.
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References

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Keywords:

pregnancy failure; miscarriage; threatened abortion; ultrasound; anembryonic; embryonic demise

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