Image Presentation

Structural Anomalies in Early Embryonic Death

A 3-Dimensional Pictorial Essay
Bryann Bromley, MD, Thomas D. Shipp, MD, Beryl R. Benacerraf, MD

Objective. The purpose of this pictorial essay was to determine whether 3-dimensional (3D) surface rendering of a dead first-trimester embryo can provide any information for the loss. Methods. Threedimensional surface rendering was performed on a collection of dead first-trimester embryos with crown-rump lengths between 12 and 27 mm. These were compared with 2-dimensional (2D) images of the same embryos and with 2D images and 3D surface renderings of normally developing embryos. Results. Surface rendering of dead embryos showed a variety of abnormalities in the contour and limb formation. Conclusions. The use of 3D sonography may provide insight into the etiology of firsttrimester embryonic death. Key words: embryonic death; malformation; 3-dimensional sonography.

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Abbreviations CRL, crown-rump length; 3D, 3-dimensional; 2D, 2dimensional Received September 23, 2009, from the Departments of Radiology and Obstetrics and Gynecology, Brigham and Womens Hospital, and Departments of Radiology and Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts USA. Revision requested October 20, 2009. Revised manuscript accepted for publication December 8, 2009. Guest Editor: Alfred Z. Abuhamad, MD. Address correspondence to Bryann Bromley, MD, Diagnostic Ultrasound Associates, PC, 333 Longwood Ave, Suite 400, Boston, MA 02115 USA. E-mail: bbsono@aol.com

pontaneous abortion or miscarriage is one of the more frequently encountered complications of early pregnancy, occurring in 15% to 20% of clinically recognized pregnancies.1 Recurrent pregnancy loss is experienced by 1% of reproductive-age women.2 The risk of spontaneous abortion increases with advancing maternal age from 20% at age 35 years to 40% by age 40 years.3 Chromosomal abnormalities account for approximately 50% of all early pregnancy losses, the risk being highest at the earliest gestational ages.4 Structural abnormalities are reported in 16.5% of spontaneously aborted embryos and fetuses examined pathologically at less than 13 weeks gestation.5 In many patients, no etiology for the pregnancy loss is ever determined.6 The criteria for identifying an early pregnancy failure have been clearly delineated.7 Often pregnancy losses occur at an early gestational age when the gestational sac is identified but no embryo is seen. The remaining losses are identified when there is an embryonic pole of 5 mm or longer without any cardiac activity. In the event that an embryo is identified, it may be possible to visualize structural abnormalities that potentially could provide insight as to the etiology of the death.

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In most cases in which an embryonic death is identified, 2-dimensional (2D) sonography is unable to provide insight as to the potential etiology of the death. In contrast, 3-dimensional (3D) sonography with surface rendering allows us to evaluate the contour of the embryo rather than a simple cross section and may provide valuable information as to morphologic abnormalities that may have contributed to the death of the embryo. This pictorial essay is presented to highlight some of the findings that may be elicited from a dead embryo when 3D surface rendering is performed on the embryo.

Materials and Methods

The collection of patients presented were referred for prenatal sonography in the first trimester of pregnancy because of bleeding, assessment of embryonic cardiac activity, or dating and had a diagnosis of an embryonic death by standard 2D sonographic criteria.7 All embryos had a crownrump length (CRL) between 12 and 27 mm and underwent both transabdominal and transvaginal imaging. It is our routine scanning protocol to perform a 3D evaluation of all embryos in the first trimester as part of our sonographic evaluation. Sonographic examinations were performed with Voluson 730 and E8 systems (GE Healthcare, Milwaukee, WI) using a transvaginal 4- to 7-MHz probe. The pregnancy termination method was at the discretion of the managing obstetrician, and in none of our cases was pathologic evaluation of the embryo possible. After the acute patient care issues were concluded, we reviewed the 3D surface renderings attained on the embryos to evaluate whether there were identifiable abnormalities in the embryonic contour to suggest a possible structural etiology for the death. The 3D images of the dead embryos were compared with similar images of normally developing embryos at similar gestational ages and CRLs.

Figure 1 shows 2D images and corresponding 3D surface renderings of normally developing embryos with CRLs of 14 mm (Figure 1, A and B) 17 mm (Figure 1, C and D), and 20 mm (Figure 1, E and F and 23 mm (Figure 1G). Figures 29 show , corresponding images of 8 dead embryos with CRLs of 12 to 27 mm. The dead embryos had a characteristic washed-out ground glass appearance on the 2D images, with no contour abnormalities appreciated. By contrast, 3D surface rendering allowed the identification of abnormalities in the contour. The most commonly identified abnormalities included abnormal curvature of the spine, prominent cervical flexure, and facial anomalies. None of the abnormalities with the exception of the conjoined twins shown in Figure 9 were identified on standard 2D sonography.

Discussion
Miscarriage is a common event complicating human reproduction. Although many early pregnancy losses are the result of chromosomal anomalies, numerous other factors, such as mllerian duct anomalies, thrombophilias, infections, autoimmune disorders, and environmental exposures, are associated with miscarriage.6 Most patients with an embryonic death do not undergo karyotyping or pathologic evaluation of the conceptus, likely because of maceration associated with pregnancy termination procedures and resource constraints. In many patients, the etiology is never determined, and counseling of these distraught parents is based on the unknown. The loss of a wanted pregnancy is a heart-wrenching experience for most couples, and any information to explain the occurrence might aid the healing process. Sonography in both 2D and 3D modes and power Doppler assessment have been used to identify pregnancies at increased risk for miscarriage. Parameters examined have included the heart rate, sac size and volume, yolk sac dimensions, hematoma size, and blood flow characteristics.813 Although the clinical implications of these findings are useful in predicting which pregnancies with heartbeats present are likely to fail, they have not addressed the possible structural etiologies associated with embryonic death. Unfortunately, when the embryonic heartbeat
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Results
Population characteristics, including maternal age, indication for referral, clinical gestational age, CRL, and pathologic reports, are shown in Table 1.
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Table 1. Characteristics of Embryos

Patient (MA, y) Indication CRL, mm GA-CRL, wk/d GA-LMP, wk 2D 3D Pathology

2 (30) 3 4 5 6 7 8 9 (42) (40) (37) (34) (30) (34) (39)

Viability No EH Bleeding Dating No EH No EH No EH No EH

22 12 16 15 18 19 22 27

8/5 7/2 8/0 7/6 8/1 8/2 8/5 9/2

12 8.5 8 10 11 10 NA 10

Ground glass Ground glass Ground glass Ground glass Ground glass Ground glass Ground glass Conjoined, ground glass

Facial cleft Angled spine, small head Abnormal head, neck, limbs Hypertelorism, abnormal spine Abnormal limbs, face Kinked spine Abnormal face, spine Conjoined

Fragmented embryo, placenta Fragmented placenta Villi, decidua necrotic Immature placenta Villi Immature placenta Immature placenta Fragmented embryo, placenta

Patient numbers correspond to figures. EH indicates embryonic heartbeat; GA, gestational age; LMP, last menstrual period; MA, maternal age; and NA, not available.

ceases, the 2D sonographic texture of the embryo becomes more homogeneous, with a faded ground glass appearance that makes it impossible to identify anatomic landmarks. Threedimensional sonography provides the ability to image the surface contour of the embryo and thus allows us to visualize the embryo from a different viewpoint than in 2D slices taken through the dead embryo. This ability allows us to compare the appearance of a dead embryo with the contour of a normally developing embryo, thus allowing recognition of areas of potential malformation. Careful attention to gestational age at the time of death is critical because the embry-

onic contour varies with the age of the embryo. The images provided in this presentation show that the 3D surface appearance of a dead embryo provides additional information about possible structural malformation that may be associated with death. The embryologic development that occurs between CRLs of 13 and 23 mm includes refinement of facial features. The eyelid folds begin to form, and the tip of the nose becomes discrete. The eyes move medially on the face, as do the nostrils. The arms begin to bend at the elbows. In a normally developing embryo at this stage, cervical flexure is identified, which corresponds

Figure 1. A and B, Two-dimensional image (A) and corresponding 3D surface rendering (B) of a normally developing embryo with a CRL of 14 mm showing the outer contour (continued).

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Figure 1. (continued) Two-dimensional (C) and corresponding 3D surface rendering (D) of a normally developing embryo with a CRL of 17 mm showing the outer contour, including the early limb buds. E and F, Transvaginal 2D image (E) and corresponding 3D surface rendering (F) of a normally developing embryo with a CRL of 20 mm. The developing hindbrain (1), eye (2), and arm (3) are indicated. The rounded structure under the embryo (4) represents the surface of the yolk sac. G, Frontal 3D surface rendering of a 23-mm embryo showing the locations of the eyes (arrows).

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Figure 2. A, Transvaginal 2D image of a dead embryo with a CRL of 22 mm. Note the ground glass appearance. B, Corresponding 3D surface rendering revealing a markedly abnormal face with a large cleft (arrows).

to the developing hindbrain. This flexure is evident on the contour of the embryo and resolves by the end of the embryonic period.14 In the group of dead embryos described above, abnormalities in the face and spinal contour and a small head size were evident. The specific anomalies were not able to be determined, but certainly the embryonic contour appeared abnormal. Limitations of this presentation include the fact that it is simply a collection of cases rather than a prospective study; therefore, the inci-

dence of these 3D surface anomalies in dead embryos cannot be determined. Additionally, the lack of pathologic correlation with the 3D surface images of the dead embryos is unfortunate. The recovered products of conception did not provide any pathologic information. Nevertheless, the images obtained by 3D surface rendering may offer information otherwise unobtainable regarding the etiology of the loss, which may be of benefit in helping patients in this difficult situation.

Figure 3. A, Transvaginal 2D image of a dead embryo with a CRL of 12 mm showing the typical ground glass appearance. B, Corresponding 3D surface rendering revealing a sharply angulated spinal curvature (1) and a small cephalic contour (2).

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Figure 4. A, Two-dimensional image of a dead embryo with a CRL of 16 mm showing the ground glass appearance. B, Corresponding 3D surface rendering revealing an abnormally shaped head (1), a curved, angulated spine (2), and abnormally shaped short extremities (3).

Figure 5. A, Transvaginal 2D image of a dead embryo with a CRL of 15 mm showing the ground glass appearance. B, In the 3D surface-rendered frontal view, the embryo is shown to have hypertelorism (arrows). C, Sagittal 3D view of the embryo showing abnormally pronounced flexure at the level of the hindbrain (arrow).

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Figure 6. A, Transvaginal 2D image of a dead embryo with a CRL of 18 mm showing the ground glass appearance. B, Corresponding 3D surface rendering revealing abnormal limbs (arrows).

B
Figure 7. A, Transvaginal 2D imaging showing a 19-mm embryonic pole. B, Corresponding 3D surface rendering revealing very prominent cervical flexure (arrow).

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B
Figure 8. A, Transvaginal 2D image of an embryo with a CRL of 22 mm without cardiac activity. B, Corresponding 3D surface rendering revealing prominent cervical flexure (arrow) and abnormal-appearing limbs. C, Frontal view of the embryo showing a very abnormal facial appearance.

Figure 9. A, Transvaginal 2D image of an embryo with a CRL of 27 mm and an abnormal contour. B, Corresponding 3D surface rendering confirming the diagnosis of conjoined twins.

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