The First Trimester - Clinical Tree

Summary of Key Points

First-trimester development follows a predictable pattern on first-trimester ultrasound.
Some ultrasound findings are definitive for early pregnancy failure, whereas others are suggestive and require follow-up.
Ultrasound is vital in the diagnosis of ectopic pregnancy in typical and atypical locations.
Gestational trophoblastic disease is composed of four entities, and ultrasound is helpful in their diagnosis and management.

The first trimester of pregnancy is a period of rapid change that spans fertilization, formation of the blastocyst, implantation, gastrulation, neurulation, the embryonic period (weeks 6-10), and early fetal life. First-trimester sonographic diagnosis traditionally focused on evaluation of growth by serial examination to differentiate normal from abnormal gestations. This has changed since the advent of transvaginal sonography (TVS), which affords enhanced resolution over transabdominal sonography (TAS), with earlier visualization of the gestational sac and its contents, earlier identification of embryonic cardiac activity, and improved visualization of embryonic and fetal structures.

Despite these technologic improvements, it is important to set clinically relevant and realistic goals for first-trimester sonographic diagnosis. Most examinations are requested because the patient has vaginal bleeding or pain, or a palpable mass has been identified on physical examination. Ultrasound in the first trimester is often requested to diagnose early pregnancy failure or an ectopic pregnancy.

The goals of first-trimester sonography include (1) visualization and localization of the gestational sac (intrauterine or ectopic pregnancy) and (2) early identification of embryonic demise and other forms of nonviable gestation. It also seeks to identify those pregnancies that are at increased risk for early pregnancy failure. First-trimester ultrasound accurately dates the duration or menstrual/gestational age of the pregnancy and assists in early diagnosis of fetal abnormalities, including identification of embryos more likely to be abnormal, based on secondary criteria (e.g., abnormal yolk sac). In multifetal pregnancies, first-trimester ultrasound can be used to determine the number of embryos and the chorionicity and amnionicity.

Current trends in ultrasound late in the first trimester focus on nuchal translucency screening combined with maternal age and maternal serum screening to determine the risk of chromosomal abnormalities and structural anomalies. Associated with the increased emphasis on late first-trimester ultrasound and first-trimester screening, there is an opportunity to visualize fetal anomalies earlier than at the time of the standard 18- to 20-week scan. First-trimester diagnosis of specific anomalies is discussed in the chapters covering those organ systems.

As experience with early first-trimester ultrasound evolves, reliable sonographic indicators of ectopic pregnancy and embryonic demise have been established. The accuracy of some sonographic signs used as indicators of the presence of a live embryo or of embryonic demise depends on the use of modern, high-resolution ultrasound equipment and the operator's expertise. Published values in the literature based on data using high-frequency transducers cannot be applied to lower-resolution 5.0-MHz transducers. The TVS signs listed in this chapter assume the use of modern equipment with a transducer frequency of at least 7 to 8 MHz, with meticulous scanning technique. Transducers with frequencies of 10 MHz or higher can provide improved spatial resolution, identifying abnormal and normal features at even earlier points in pregnancy. Nyberg and Filly emphasize that experienced physicians who interpret ultrasound rarely rely on a single parameter and simultaneously consider multiple variables to create a diagnostic impression.

Maternal Physiology and Embryology

All dates presented in this chapter are in menstrual age or gestational age, in keeping with the radiologic and obstetric literature, rather than in embryologic age, as used by embryologists. This can be counted as follows:

Gestational age = Conceptual age + 2 weeks

$Gestational age = Conceptual age + 2 weeks$

Early in the menstrual cycle, the pituitary secretes rising levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which cause the growth of 4 to 12 primordial follicles into primary ovarian follicles ( Fig. 30.1 ). When a fluid-filled cavity or antrum forms in the follicle, it is referred to as a secondary follicle. The primary oocyte is off to one side of the follicle and surrounded by follicular cells or the cumulus oophorus. One follicle becomes dominant, bulges on the surface of the ovary, and becomes a “mature follicle” or graafian follicle. It continues to enlarge until ovulation, with the remainder of the follicles becoming atretic. The developing follicles produce estrogen. The estrogen level remains relatively low until 4 days before ovulation, when the dominant or active follicle produces an estrogen surge, after which an LH and prostaglandin surge results in ovulation. Ovulation follows the LH peak within 12 to 24 hours. Actual expulsion of the oocyte from the mature follicle is aided by several factors, including the intrafollicular pressure, possibly contraction of the smooth muscle in the theca externa stimulated by prostaglandins, and enzymatic digestion of the follicular wall.

FIG. 30.1, Schematic Drawing of Interrelationships Among the Hypothalamus, Pituitary Gland, Ovaries, and Endometrial Lining.

Ovulation occurs on approximately day 14 of the menstrual cycle with expulsion of the secondary oocyte from the surface of the ovary. In women with a menstrual cycle longer than 28 days, this ovulation occurs later, so that the secretory phase of the menstrual cycle remains at about 14 days. After ovulation, the follicle collapses to form the corpus luteum, which secretes progesterone and, to a lesser degree, estrogen. If a pregnancy does not occur, the corpus luteum involutes. In pregnancy, involution of the corpus luteum is prevented by human chorionic gonadotropin (hCG), which is produced by the outer layer of cells of the gestational or chorionic sac (syncytiotrophoblast).

Before ovulation, endometrial proliferation occurs in response to estrogen secretion ( Fig. 30.1 ). After ovulation, the endometrium becomes thickened, soft, and edematous under the influence of progesterone. The glandular epithelium secretes a glycogen-rich fluid. If pregnancy occurs, continued production of progesterone results in more marked hypertrophic changes in the endometrial cells and glands to provide nourishment to the blastocyst. These hypertrophic changes are referred to as the decidual reaction and occur as a hormonal response regardless of the site of implantation, intrauterine or ectopic.

Oocyte transport into the fimbriated end of the fallopian tube occurs at ovulation as the secondary oocyte is expelled with the follicular fluid and is “picked up” by the fimbria. The sweeping movement of the fimbria, the currents produced by the action of the cilia of the mucosal cells, and the gentle peristaltic waves from contractions of the fallopian musculature all draw the oocyte into the tube.

The mechanism of sperm transport is regulated to maximize the chance of fertilization and ensure the most rigorous sperm will be available. From 200 to 600 million sperm and the ejaculate fluid are deposited in the vaginal fornix during intercourse. Sperm must move through the cervical canal and its mucous plug, up the endometrial cavity, and down the fallopian tube to meet the awaiting oocyte within the distal third or ampullary portion of the fallopian tube. Sperm were thought to move primarily using their tails, although they travel at 2 to 3 mm per minute, which would take about 50 minutes to travel the 20 cm to their destination. Settlage et al. found motile sperm within the ampulla between 5 and 10 minutes after deposition near the external cervical os. If inert particles such as radioactive macroaggregates or carbon particles are placed near the external os, they too will be picked up and transported up the uterus and down the tubes. Contractions of the inner layer of myometrium are believed to create a negative pressure strong enough to suck up particles and move them up the endometrial canal. These contractions have been demonstrated in nonpregnant women and increase in strength and frequency to peak at 3.5 contractions per minute at ovulation.

Fertilization occurs on or about day 14 as the mature ovum and sperm unite to form the zygote in the outer third of the fallopian tube ( Fig. 30.2 ). Cellular division of the zygote occurs during transit through the fallopian tube. By the time the conceptus enters the uterus, about day 17, it is at the 12- to 15-cell stage (morula). By day 20, the conceptus has matured to the blastocyst stage. The blastocyst is a fluid-filled cyst lined with trophoblastic cells that contain a cluster of cells at one side called the inner cell mass. On day 20, the blastocyst at the site of the inner cell mass burrows through the endometrial membrane into the hyperplastic endometrium, and implantation begins ( Fig. 30.3A ).

FIG. 30.2, Diagram of Ovarian Cycle, Fertilization, and Human Development to the Blastocyst Stage.

FIG. 30.3, Implantation of the Blastocyst Into Endometrium.

Implantation is completed by day 23 as the endometrial membrane re-forms over the blastocyst ( Fig. 30.3B ). During implantation, the amniotic cavity forms in the inner cell mass. A bilaminar embryonic disk separates the amniotic cavity from the exocoelomic cavity. The primary (primitive) yolk sac forms at about 23 days of gestational age as the blastocyst cavity becomes lined by the exocoelomic membrane and hypoblast. As the extraembryonic coelom forms, the primary yolk sac is pinched off and extruded, resulting in the formation of the secondary yolk sac ( Fig. 30.4 ). Standard embryology texts indicate that the secondary yolk sac forms at approximately 27 to 28 days of menstrual age, when the mean diameter of the gestational sac is approximately 3 mm. It is the secondary yolk sac, rather than the primary yolk sac, that is visible with ultrasound. For the remainder of this chapter, the term yolk sac is used to refer to the secondary yolk sac. The extraembryonic coelom becomes the chorionic cavity.

FIG. 30.4, Formation of Secondary Yolk Sac.

Later, because of differential growth, the yolk sac comes to lie between the amnion and chorion. During week 4, there is rapid proliferation and differentiation of the syncytiotrophoblast, forming primary chorionic villi. Traditional thinking that the syncytiotrophoblastic cells invade the maternal endometrial vessels, leaving maternal blood to bathe the trophoblastic ring, has been challenged. Hustin compared TVS to hysteroscopy of the placenta, chorionic villous sampling tissue, and hysterectomy specimens with an early pregnancy in situ. Before 12 weeks, the intervillous space contains no blood, only clear fluid, and on histologic examination, the villous tissue is separated from the maternal circulation by a continuous layer of trophoblastic cells. Only after the third month does the trophoblastic shell become broken and the maternal circulation become continuous with the intervillous space. Furthermore, at weeks 8 and 9 of gestation, the trophoblastic shell forms plugs within the spiral arteries, allowing only filtered plasma to permeate the placenta. In two-thirds of abnormal pregnancies, the trophoblastic shell is thinner and fragmented, and the trophoblastic invasion of the spiral arteries is reduced or absent.

Vascularization of the placenta occurs at the beginning of the fifth week. Oh et al. showed significant increases in sac size from 5 weeks onward in normal intrauterine pregnancy (IUP) versus pregnancy failure. The rationale for placental vascularization was based on early work by Folkman, who showed that tumors can grow to a size of 3 mm being nourished only by diffusion. To exceed this size, cells must recruit host blood vessels, or the cells at the center will receive inadequate nutrition. Similarly, the rapidly growing embryonic implantation must be vascularized by the 3-mm stage that occurs at 5 weeks' gestation.

During the fifth week, the embryo is converted by the process of gastrulation from a bilaminar disk to a trilaminar disk with the three primary germ cell layers: ectoderm, mesoderm, and endoderm. During gastrulation, the primitive streak and notochord form. The primitive streak gives rise to the mesenchyme, which forms the connective tissue of the embryo and stromal components of all glands.

The formation of the neural plate and its closure to form the neural tube is referred to as neurulation. This process begins in the fifth week in the thoracic region and extends caudally and cranially, resulting in complete closure by the end of the sixth week (day 42). Failure of closure of the neural tube results in neural tube defects.

During the fifth week, two cardiac tubes (the primitive heart) develop from splanchnic mesodermal cells. By the end of the fifth week, these tubes begin to pump into a primitive paired vascular system. By the end of the fifth week, a vascular network develops in the chorionic villi that connect through the umbilical arteries and vein to the primitive embryonic vascular network.

Essentially all internal and external structures appear in the adult form during the embryonic period, which ends at 10 menstrual weeks. By the end of the sixth week, blood flow is unidirectional, and by the end of the eighth week, the heart attains its definitive form. The peripheral vascular system develops slightly later and is completed by the end of the tenth week. The primitive gut forms during week 6. The midgut herniates into the umbilical cord from week 8 through the end of week 12. The rectum separates from the urogenital sinus by the end of week 8, and the anal membrane perforates by the end of week 10. The metanephros, or primitive kidneys, ascend from the pelvis, starting at approximately week 8, but do not reach their adult position until week 11. Limbs are formed with separate fingers and toes. Almost all congenital malformations except abnormalities of the genitalia originate before or during the embryonic period. External genitalia are still in a sexless state at the end of week 10 and do not reach mature fetal form until the end of week 14.

Early in the fetal period, body growth is rapid and head growth relatively slower, with the crown-rump length (CRL) doubling between weeks 11 and 14.

Sonographic Appearance of Normal Intrauterine Pregnancy

Gestational Sac

Implantation usually occurs in the fundal region of the uterus between day 20 and day 23. In a study of early implantation sites in 21 patients, it was found that implantation occurs most frequently on the uterine wall ipsilateral to the ovulating ovary and least often on the contralateral wall. In addition, in a study of predominant sleeping positions in the peri-implantation period, Magann et al. found that the 33% of women who slept prone were most likely to have a high or fundal implantation than those who slept on their back or side. The latter groups predominantly had implantations corresponding to their resting posture.

At 23 days, the entire conceptus measures approximately 0.1 mm in diameter and cannot be imaged by TAS or TVS techniques. The earliest sonographic sign of an IUP was described by Yeh et al., who identified a focal echogenic zone of decidual thickening at the site of implantation at about to 4 weeks of gestational age. This sign is nonspecific and of limited diagnostic value.

The first reliable gray-scale evidence of an IUP is visualization of a small (1-2 mm fluid collection surrounded by an echogenic rim) gestational sac within the thickened decidua. Yeh et al. originally identified this sign, referred to as the intradecidual sign, which is seen at about 4.5 weeks' gestation. An intradecidual gestational sac should be eccentrically located within the endometrium. It is important to ensure that the sac abuts the endometrial canal to distinguish an intrauterine gestational sac from a decidual cyst.

The intradecidual sign was originally described on TAS, with a sensitivity of 92%, specificity 100%, and overall accuracy of 93% for distinguishing between early IUP and ectopic pregnancy. Chiang et al. looked at this sign using TVS and found overall sensitivity of 60% to 68%, specificity of 97% to 100%, and overall accuracy of 67% to 73%, indicating that the sign, when present, is useful for diagnosing an IUP. When absent, it does not reliably exclude an IUP. It is usually possible to demonstrate an early IUP as a small intradecidual sac between and 5 weeks' gestational age using TVS ( Figs. 30.5 and 30.6 ). Using a high-frequency (7.5-10 MHz) TVS, Oh et al. were able to identify a gestational sac in all 67 patients scanned between 28 and 42 days' gestational age ( mean sac diameter [MSD] between 28 and 35 days was 2.6 mm).

FIG. 30.5, Intradecidual Sac Sign at 32 Days.

The double-decidual sign (also called double decidual sac sign) was described by Bradley et al. and Nyberg et al. as a method for distinguishing between an early IUP and an endometrial fluid collection of other origin, such as the pseudosac of an ectopic pregnancy. A well-defined double-decidual sign is an accurate predictor of the presence of an IUP. A vague or absent double-decidual sign should be considered nondiagnostic because it does not reliably exclude an IUP.

The endometrium in the pregnant state is called the decidua capsularis, decidua vera, and decidua basalis. The double-decidual sign is based on visualization of the gestational sac as an echogenic ring formed by the decidua capsularis and chorion laeve eccentrically located within the decidua vera ( Fig. 30.6 ), forming two echogenic rings. The outer ring is formed by the echogenic endometrium of the lining of the uterus. The decidua basalis–chorion frondosum (future placenta) may also be visualized as an area of eccentric echogenic thickening. The double-decidual sign was initially described, and is considered most useful, on TAS. It can usually be identified by about 5.5 to 6 weeks' gestational age and is useful in establishing an intrauterine gestation prior to TAS ability to visualize the yolk sac. It is almost always resolvable by the time the gestational sac reaches 10 mm, at which point the yolk sac is typically visible by TVS, thus diminishing the usefulness of this finding.

Parvey et al. found a double-decidual sign in only 53% of early pregnancies with no yolk sac or embryo present. They also assessed visualization of the echogenic chorionic rim alone as a sign of IUP and found its presence in 64% of cases. It was more clearly defined in later pregnancies with a higher β-hCG level (mean, 16,082 mIU/mL) and thin, less clearly defined, or even absent in the earliest pregnancies. Using a higher-frequency 10-MHz transvaginal transducer to scan patients who had a positive pregnancy test and only a small (<1 cm) intrauterine “fluid collection” seen with a 6- to 7-MHz transducer, Benacerraf et al. were able to improve their diagnostic confidence in eight patients with an IUP. This demonstrates the need to scan TVS with a high-frequency transducer when an early pregnancy is in question. Even with use of modern TVS equipment, the double-decidual sign is absent in at least 35% of intrauterine gestational sacs.

The normal gestational sac is round in the very early stages and implants immediately beneath the thin, echogenic endometrial stripe (see Fig. 30.5 ). As it enlarges, the sac often has a somewhat oval shape because of the pressure exerted by the muscular uterine walls ( Fig. 30.7 ). It can be distorted during TVS by compressing the uterus with the vaginal probe. The gestational (or chorionic) sac is filled with extracoelomic or chorionic sac fluid, which is normally weakly reflective and more echogenic than the amniotic fluid. This difference is best appreciated if the system gain is increased. The low-level echoes within the chorionic fluid are accentuated, and yet the amniotic fluid remains echo free ( Fig. 30.8 ). The low-level echoes are likely caused by the relatively thick proteinaceous material in chorionic fluid.

Some researchers have investigated using color flow Doppler sonography to help identify the presence of an early IUP. Emerson et al. found that the detection of peritrophoblastic flow of high velocity and low impedance increased the sensitivity of detection of IUP from 90% to 99%. Parvey et al. found this flow pattern in only 15% of IUPs without a visible yolk sac or embryo. They considered that combining the Doppler findings with the sonographic identification of inner chorionic rim would yield a high sensitivity and specificity of over 90%. However, this exposes the early IUP to the increased power deposition of Doppler scanning (see Chapter 29 ). Therefore Doppler should not be routinely performed when assessing the early IUP. However, when scanning in the adnexal region, use of Doppler and associated power deposition is not a concern, because the first-trimester pregnancy (if ectopic) is nonviable (and because any IUP would be out of the field of insonation).

β-hCG and Early Pregnancy Ultrasound

Serum hCG levels perform an important complementary role with ultrasound in the evaluation of early pregnancy. Levels using the serum beta subunit of human chorionic gonadotropin (β-hCG) provide a reproducible value that can help guide management in clinical practice.

A negative serum β-hCG level excludes pregnancy in a young woman with pain or bleeding. The serum β-hCG test yields positive results at approximately 23 days of gestational age, before a normal intrauterine gestational sac may be imaged with TVS. A disproportionately lower than expected β-hCG level is an indicator of a poor prognosis. The World Health Organization (WHO) has issued several sets of standards for β-hCG, calibrated in International Units (IU). Over the years, β-hCG levels have been measured using the first International Reference Preparation (IRP), the Second International Standard (IS), the Third IS, and the Fourth IS. The Second IS produces values that are approximately half that of the First IRP and Third and Fourth IS. The WHO recommends that the Third and Fourth IS should be used for calibration of immunoassays.

In a literature review, Nyberg and Filly noted the importance of the appropriate use of a threshold level and a discriminatory level of β-hCG for the appearance of a gestational sac. The threshold level identifies the earliest one can expect to see a sac, and the discriminatory level identifies when one should always see the sac. Although the menstrual history provides useful information early in a woman's obstetric care, because of the variability in the timing of ovulation and the unreliability of menstrual history, discriminatory levels based on history are of limited clinical use.

A gestational sac can often be visualized sonographically at low serum β-hCG levels. As TVS has improved, threshold values have dropped to as low as 390 mIU/mL. Extensive efforts have been made to identify a discriminatory level for the serum β-hCG, defined as the level of serum β-hCG above which sonographers should always visualize an intrauterine sac on ultrasound to be considered normal. Work by Barnhart indicated that this level, using TVS, should be set at 1000 to 2000 mIU/mL. However, additional studies have shown that a single value of β-hCG is of limited value. Mehta at el. showed that although the absence of a visible sac at a β-hCG level of 2000 mIU/mL is suggestive of an abnormal outcome, it is not diagnostic, as 33% (17 of 51 in her series) of such early pregnancies went on to have normal outcomes.

Discriminatory levels can be used to guide management but cannot be used as absolute indicators that the absence of a sonographically demonstrable gestation sac is abnormal. Serial β-hCG measurements are usually more helpful than a single measurement in identifying abnormal from normal pregnancy, and ultrasound can document important diagnostic features regardless of the exact β-hCG value.

Barriers to Use of Strict β-hCG Thresholds in Determination of Pregnancy

Resolution of the ultrasound scanner
Patient body habitus
Position of the uterus
Type of hormonal assay
Experience of the sonographer
Masses such as fibroids
Multiple gestations

Yolk Sac

At 4 weeks' menstrual age, the primary yolk sac begins to regress and the secondary yolk sac develops. The secondary yolk sac is the first structure to be seen normally within the gestational sac. Using TAS, it is often seen when the MSD is 10 to 15 mm and should typically be visualized by an MSD of 20 mm. TVS allows earlier and more detailed visualization of the yolk sac ( Figs. 30.6 and 30.9 ), which is typically visualized by an MSD of 8 mm. However, the visualization of a yolk sac without an embryonic pole occurs only for a brief period of time. In patients being scanned for pregnancy of unknown viability, the MSD of 25 is used as the threshold, with need to visualize an embryo at this time.

The demonstration of a yolk sac may be critical in differentiating an early intrauterine gestational sac from a pseudosac. Although the double-decidual sign is not 100% specific for presence of an IUP, the identification of a yolk sac within the early gestational sac is diagnostic of IUP. The yolk sac plays an important role in human embryonic development. While the placental circulation is developing, the yolk sac plays a role in transfer of nutrients to the developing embryo in the third and fourth weeks. Angiogenesis occurs in the wall of the yolk sac in the fifth week. The mesenchymal cells or angioblasts aggregate to form “blood islands”; a cavity forms within these islands, which fuse with others to form networks of endothelial channels. Vessels extend into adjacent areas by endothelial budding and fusion with other vessels. This vascular network in the wall of the yolk sac eventually joins the embryonic circulation via the paired vitelline arteries and veins through a stalk called the vitelline duct. Hematopoiesis occurs first in the well-vascularized extraembryonic mesoderm covering the yolk sac wall in the fifth week, in the liver in the eighth week, and later in the spleen, bone marrow, and lymph nodes. The dorsal part of the yolk sac is incorporated into the embryo as primitive gut (foregut, midgut, and hindgut) in the sixth week. The yolk sac remains connected to the midgut by the vitelline duct ( Fig. 30.10 ).

Lindsay et al. reported that the yolk sac grows at a rate of 0.1 mm per millimeter of MSD growth when the MSD is less than 15 mm, then slows to 0.03 mm. The upper limit of normal for yolk sac diameter between 5 and 10 weeks of gestational age is 5.6 mm.

The number of yolk sacs present can be helpful in determining amnionicity of a multifetal pregnancy ( Fig. 30.11 ). In general, the number of yolk sacs and the number of amniotic sacs are the same. In a monochorionic monoamniotic (MCMA) twin gestation, there will be two embryos, one chorionic sac, one amniotic sac, and one yolk sac. Levi et al. examined four MCMA twin pregnancies, all with a single yolk sac. One was a conjoined twin and one a twin ectopic, with both pregnancies terminated. The other two pregnancies delivered normally at 34 weeks. Of the four cases, two had a larger-than-normal yolk sac (>5.6 mm), and one yolk sac was irregular in contour. Therefore in MCMA twins, a single, large, or normal-sized yolk sac with two live embryos can result in a normal twin delivery.

FIG. 30.11, Early Monochorionic Diamniotic (MCDA) Twins.

Embryo and Amnion

Visualization of the amnion in the absence of an embryo usually occurs in intrauterine embryonic death as a result of resorption of the embryo ( Fig. 30.12 ).

Amniotic fluid is a colorless, fetal dermal transudate; as the skin cornifies and the kidneys begin to function, at about 11 weeks, it becomes pale yellow. The amnion becomes visible when the embryo has a CRL of 2 mm at 6 weeks. The cavity becomes almost spherical by about 7 weeks, likely a result of the more rapid increase in fluid volume relative to the growth of the sac membrane to accommodate it. The actual rate of fluid increase is more rapid after about 9 weeks ( Fig. 30.13 ), when urine is produced. Fluid accumulates at about 5 mL per day at 12 weeks. The amniotic cavity expands to fill the chorionic cavity completely by week 16. It is therefore normal to identify the amnion as a separate membrane or sac within the chorionic cavity before 16 weeks ( Fig. 30.14 ). Occasionally, the amnion and chorionic membranes may fail to be juxtaposed at week 16 (so-called unfused amnion ), and separation of these membranes may persist for a short time.

FIG. 30.13, Normal 9-Week 4-Day Gestation.

Iatrogenic or spontaneous rupture of the amniotic membrane in the first trimester is a rare occurrence and even more rarely results in the amniotic band sequence. This rupture may result in retraction of the amnion in part or in whole, up to the base of the umbilical cord where the amnion and chorion are adherent. More often, the floating amniotic membranes do not adhere to the fetus, and no fetal anomalies occur.

Embryonic Cardiac Activity

Using TVS, an embryo with a CRL as small as 1 to 2 mm may be identified immediately adjacent to the yolk sac ( Fig. 30.15 ). In normal pregnancies the embryo can be identified in gestational sacs as small as 10 mm and should always be identified when the MSD is equal to or greater than 25 mm with optimal scanning parameters and high-resolution TVS.

FIG. 30.15, Normal Embryo With Early Cardiac Activity.

Embryologic data suggest the tubular heart begins to beat at 36 to 37 days' gestational age. Cadkin and McAlpin described cardiac activity adjacent to the yolk sac before the embryo can be fully visualized at the end of the fifth week. Ragavendra et al. placed a 12.5-MHz endoluminal catheter transducer into the endometrial canal adjacent to the gestational sac. They identified cardiac activity in an embryo with a CRL of 1.5 mm and resolved the two walls of the heart, seen only as a tube. Using TVS, cardiac activity is typically seen by the time an embryo is 2 mm in size, and is almost always seen by 5-mm CRL. However, for strict diagnosis of nonviable pregnancy the threshold is set at 7 mm CRL. Normal embryonic cardiac activity is greater than 100 beats per minute (bpm) ( Video 30.1) when the embryo is less than 6.3 weeks and 120 bpm at or beyond 6.3 weeks. When embryonic cardiac activity is visualized and the rate is less than 100 bpm, then follow-up should be obtained. We have seen pregnancies with small embryos of 1–2 mm in size with heart rates of 80–99 bpm with normal follow-up (see Fig. 30.15 ).

Umbilical Cord and Cord Cyst

The umbilical cord is formed at the end of the sixth week (CRL = 4.0 mm) as the amnion expands and envelops the connecting stalk, the yolk stalk, and the allantois. The cord contains two umbilical arteries, a single umbilical vein, the allantois, and yolk stalk (also called the omphalomesenteric duct or vitelline duct ), all of which are embedded in Wharton jelly. The umbilical arteries arise from the internal iliac arteries and in the newborn become the superior vesical arteries and the medial umbilical ligaments. The umbilical vein carries oxygenated blood from the placenta to the fetus. The oxygenated blood is shunted through the ductus venosus into the inferior vena cava and the heart. The single left umbilical vein in the newborn becomes the ligamentum teres, which attaches to the left branch of the portal vein. The ductus venosus becomes the ligamentum venosum.

The allantois is associated with bladder development and becomes the urachus and the median umbilical ligament. It extends into the proximal portion of the umbilical cord. The yolk stalk connects the primitive gut to the yolk sac. The paired vitelline arteries and veins accompany the stalk to provide blood supply to the yolk sac. The arteries arise from the dorsal aorta to supply initially the yolk sac, then the primitive gut. The arteries remain as the celiac axis, superior and inferior mesenteric arteries supplying the foregut, midgut, and hindgut, respectively. The vitelline veins drain directly into the sinus venosus of the heart. The right vein is later incorporated into the right hepatic vein. The portal vein is also formed by an anastomotic network of vitelline veins.

The length of the umbilical cord has a close linear relationship with gestational age in normal pregnancies. Hill et al. found they could reliably measure the cord lengths in 53 embryos at 6 to 11 weeks' gestational age. Also, the cord lengths in 60% of dead embryos were more than two standard deviations (2 SD) below the value for that expected gestational age.

The width of the umbilical cord has also been measured sonographically, and Ghezzi et al. found a steady increase from 8 to 15 weeks. There was a significant correlation between cord diameter and gestational age ( r = 0.78; P < .001), CRL ( r = 0.75; P < .001), and biparietal diameter ( r = 0.81; P < .001) but no correlation with birth weight or placental weight. The cord diameter was significantly smaller by at least 2 SD in patients who developed preeclampsia or had a miscarriage.

Cysts and pseudocysts within the cord have been described in the first trimester. Cysts are usually seen in the eighth week and usually resolve by the 12th week. They are singular, closer to the embryo/fetus than the placenta, with a mean size of 5.2 mm ( Fig. 30.16 ). Cysts may originate from remnants of the allantois or omphalomesenteric duct and characteristically have an epithelial lining. It is hypothesized that the cyst is an amnion inclusion cyst that occurs as the amnion was enveloping the umbilical cord. In a series of 1159 consecutive patients scanned between 7 and 14 weeks, Ghezzi et al. found 24 cord cysts at a prevalence of 2.1%. Single cysts in the first trimester were associated with a normal outcome and a healthy infant, whereas multiple or complex cysts were associated with an increased risk of miscarriage or aneuploidy. Thus although umbilical cord cysts have been associated with chromosomal abnormalities if seen in the second and third trimesters, those seen in the first trimester typically resolve and are not associated with poor outcome.

FIG. 30.16, Umbilical Cord Cyst at 10 Weeks.

Estimation of Gestational Age

During the first trimester, gestational age can be estimated sonographically with greater accuracy than at any other stage of pregnancy. As pregnancy progresses, biologic variation results in wider variation around the mean for all sonographic parameters at a given gestational age.

Gestational Sac Size

The MSD offers an opportunity to date an early pregnancy before the embryo can be visualized. The MSD is an average of the diameter of the sac, obtained by adding the anteroposterior and craniocaudad diameters on the sagittal view of the uterus to the transverse diameter obtained on the transverse view and dividing by three ( Fig. 30.17 ). The gestational age can be predicted by MSD using the following formula: menstrual age in days = MSD in mm + 30. The MSD increases in size at a rate of 1.1 mm per day. If MSD is very small, about 2 mm, gestational age is 4 to weeks, and MSD of about 5 mm is 5 weeks. At weeks, a yolk sac appears (see Fig. 30.9A and B ). At 6 weeks, an embryo first appears adjacent to the yolk sac (see Fig. 30.15A ). When the embryo is first seen, cardiac activity is appreciated as a consistent flicker ( Fig. 30.15B and ).

FIG. 30.17, Gestational Age Established by Mean Sac Diameter (MSD).

Crown-Rump Length

Once the embryonic pole is visualized (just before 6 weeks), measurement of the CRL of the embryo is considered the most accurate method to date the pregnancy.

Early Pregnancy Failure

One of the most important roles of ultrasound in the first trimester is to identify early pregnancies that have failed or that are more likely to fail. Studies have demonstrated a 20% to 31% rate of early pregnancy loss after implantation in normal healthy volunteers. Many pregnancies abort before the pregnancy is confirmed by either ultrasound or a chemical pregnancy test. Approximately 50% of miscarriage is caused by chromosomal abnormalities. Early pathologic studies of Hertig and Rock, also showed a high frequency of morphologic abnormalities in preimplantation embryos. Loss rates are increased with increased maternal age and prior history of early pregnancy failure.

Although the etiology of first-trimester pregnancy loss is still not fully understood, there are many known and suspected causes. In a study of 232 first-trimester patients (normal, healthy women, positive urinary pregnancy test, and no vaginal bleeding) with TVS at the first visit, Goldstein determined the incidence of subsequent pregnancy loss by following all to delivery or spontaneous abortion. This group had an overall pregnancy loss rate of 11.5% in the embryonic period, (i.e., <70 days from last menstrual period). The loss rate diminished as the pregnancy progressed. The loss rate was 8.5% when a yolk sac was seen, 7.2% with an embryo of CRL less than 5 mm, 3.3% with CRL 6 to 10 mm, and 0.5% with CRL greater than 10 mm. The loss rate leveled off at 2% from 14 to 20 weeks. Therefore under the best circumstances, the pregnancy loss rate will be 11.5% overall, from 5 weeks onward. Once the embryo reaches a CRL of 10 mm, there is about a 98% chance of a successful outcome. Westin et al. confirmed that after 12 weeks menstrual age, the miscarriage rate decreases to 0.5% in low-risk women.

A patient who is in the process of a spontaneous abortion will often present with brownish spotting, a decrease in the symptoms of pregnancy (breast tenderness, nausea), and on examination, a uterus smaller than expected. The latter sign is subjective and not reliable in early gestation. Bleeding is a common complication in early pregnancy, affecting approximately 25% of women with documented pregnancies. Women who present with bleeding have a much higher incidence of pregnancy loss. In women who present with a closed cervical os and uterine bleeding in the first trimester, 50% will eventually abort. Using TVS, Falco et al. studied 270 patients with first-trimester bleeding at 5 to 12 weeks' gestation; 45% were diagnosed initially as a nonviable pregnancy or empty gestational sac. Of the remaining singletons with demonstrable fetal cardiac activity, 15% (23/149) subsequently aborted. In a later prospective study of 50 patients with MSD of 16 mm or less, no embryo, and first-trimester bleeding, Falco et al. found that 64% eventually miscarried; 13/18 (72%) of those who continued to delivery had a yolk sac seen; and 13/32 (40%) went on to fail even though a yolk sac was present. Advanced maternal age (>35) and low serum β-hCG (<1200 mIU/mL IRP) were associated with increased risk of pregnancy failure.

Table 30.1 summarizes the rate of spontaneous abortion in women with and without bleeding in early pregnancy.

TABLE 30.1

Rate of Spontaneous Abortion in Early Pregnancy

Study	Age (Wk)	Number	Indication	Abortion Rate (%)
Goldstein	5-10	232	Routine	11.5
Pandya et al.	10-13	17,870	Routine	2.8
Stabile et al.	5-16	624	Bleeding	45
Falco et al.	5-12	270	Bleeding	51.5
Falco et al.	5-12	149	Bleeding + live embryo/fetus	15
Pandya et al.	10-13	17,870	Bleeding	15.6

One theorized cause of early pregnancy failure is chromosomal anomaly in the early embryo. Sorokin et al. performed chorionic villous sampling in 795 first-trimester pregnancies and found that 35 had a nonviable pregnancy before the procedure; 19 of the 35 women had subsequent chorionic villous sampling, and all were aneuploid. Ten cases had chromosomal abnormalities, virtually always lethal in the embryonic period, and nine had defects with moderate potential for viability. Gestations with low viability potential had a larger discrepancy (23.4 ± 8.3 days) in estimated minus observed gestational age, which was significantly greater than that of gestations with moderate viability potential (8.9 ± 4.3 days; P < .001). The absence of an embryonic pole was more common in the first group. This demonstrates that the more severe the anomaly is, the more likely that very early embryonic demise or intrauterine growth restriction will occur.

Another cause of early pregnancy failure is luteal phase defect, thought to be failure of the corpus luteum to support the conceptus adequately once implantation has occurred. This may result from a shortened luteal phase in cases of ovulation induction and in vitro fertilization (IVF), or from luteal dysfunction, more frequently seen in obese women or women older than 37 years of age. Luteal phase defect has been defined as a delay of more than 2 days in histologic development of the endometrium relative to the day of the cycle. The underlying cause may be decreased hormone production by the corpus luteum, decreased levels of FSH or LH or abnormal patterns of secretion, or a decreased response of the endometrium to progesterone.

Angiogenesis of the corpus luteum may be needed for the regulation of progesterone production. Kupesic et al. found that the resistive index (RI) in intraovarian arteries in normal nongravid women dropped below 0.47 in the luteal phase compared to a group with luteal phase defect who had a high resistance throughout the menstrual cycle, with RI always above 0.50. They suggest that Doppler sonography may predict functional capacity of the corpus luteum, at least in the nongravid state. Blumenfeld and Ruach were successful in treating luteal phase defect in a group undergoing ovulation induction and in patients with previous abortions, using hCG administration twice weekly in the sixth and tenth weeks. This reduced the rate of miscarriage from 49% to 17.8% ( P < .01).

Currently, as medical management for a failed pregnancy may include intervention with misoprostol that may harm a potentially viable pregnancy, a false positive diagnosis of early pregnancy failure can lead to negative consequences. This has led to a philosophy espoused by the Society of Radiologists in Ultrasound of using conservative criteria on ultrasound for early pregnancy failure that would eliminate a false positive result. Early pregnancy failure may not always be able to be diagnosed or excluded on the basis of a single ultrasound, and follow-up studies may be necessary for conclusive diagnosis.

Diagnostic Findings of Early Pregnancy Failure

CRL of 7 mm without a heartbeat
MSD of 25 mm without an embryonic pole

Crown-Rump Length 7 mm or Greater and No Heartbeat

In patients with a sonographically demonstrable embryo, no cardiac activity is one of the most important factors in predicting pregnancy outcome. The absence of cardiac activity does not necessarily indicate embryonic demise, however, because TVS can identify a normal, very early embryo without cardiac activity.

Many studies have demonstrated that cardiac activity is expected when CRL is greater than 5 mm. Levi et al. reviewed a series of 96 patients with CRL of less than 5 mm to assess the predictive value of the presence or absence of cardiac activity using TVS. Of 71 patients available for follow-up, 46 embryos had cardiac activity, 35 progressed to at least the late second trimester, and 11 ended as first-trimester demise. Of the 25 embryos without demonstrable cardiac activity, 5 (20%) were normal and 20 (80%) ended as first-trimester embryonic deaths. Of the five normal embryos without demonstrable cardiac activity on initial TVS, three had initial CRL of less than 1.9 mm. Standard embryology texts indicate that the embryonic heart begins to beat at the beginning of the sixth week, when the CRL is 1.5 to 3 mm. Thus it is not surprising that cardiac activity may or may not be identified in normal embryos with CRL less than 2 mm. In the study by Levi et al., initial TVS assessment failed to identify cardiac activity in 2 of 25 normal embryos with CRL of 2 to 4 mm. TVS enabled correct identification of cardiac activity in 100% of normal embryos with CRL of 4 to 4.9 mm. Pennell et al. found that 16 of 18 embryos with CRL less than 5 mm had no cardiac activity on initial TVS assessment but demonstrated cardiac activity on follow-up TVS. Cardiac motion was seen on TVS in all pregnancies with CRL greater than 5 mm.

The combination of vaginal bleeding and absent cardiac activity in embryos of CRL less than 5 mm on TVS is associated with a very poor prognosis. Aziz et al. reviewed outcomes in embryos of CRL of 5 mm or less with absent cardiac activity on TVS, in women presenting with vaginal bleeding; all resulted in pregnancy failure.

Before making a diagnosis of embryonic demise, it is critical to ensure that the examination is of high quality, performed with modern equipment and an appropriate transducer frequency, and that the entire embryo is visualized. A high frame rate must be used, and the frame-averaging mode must be turned off. If there is any doubt in the diagnosis, follow-up examination should be performed. There is interobserver variability in measurement, even by experienced sonographers. In a prospective cross-sectional study on 1060 women, Abdullah et al. demonstrated that changing the CRL cutoff to greater than 7 mm would minimize the risk of a false positive diagnosis of miscarriage. A generous cutoff ensures that a desired pregnancy would not be mistakenly terminated by the administration of medication for chemical miscarriage or dilation and curettage to remove products of conception ( Fig. 30.18 , Video 30.2). It is also imperative that transmitted maternal pulsations are not mistaken for embryonic cardiac pulsations, especially when evaluating a static M-mode image to verify embryonic cardiac activity ( Figs. 30.18B and 30.19 ).

FIG. 30.18, Ultrasound Findings Diagnostic of Early Pregnancy Failure.

FIG. 30.19, M-Mode Documenting Transmitted Maternal Uterine Arterial Pulsations Mistaken for Fetal Cardiac Pulsations.

Gestational Sac Mean Sac Diameter 25 mm or Greater and No Embryo

In many patients the embryo is not visualized on the initial sonogram, and the diagnosis of pregnancy failure cannot be made on the basis of lack of cardiac activity. In these patients the diagnosis of pregnancy failure may be made based on gestational sac characteristics. The most reliable indicator of abnormal outcome based on gestational sac features is abnormal size.

Using TVS, an MSD of 8 mm or more without a demonstrable yolk sac, or 16 mm with no demonstrable embryo, are not typical and are suggestive of pregnancy failure. However, recent studies have documented gestational sacs up to 21 mm with initially no visible embryos that went on to be viable pregnancies. Most authors allow a few millimeters of leeway in MSD measurements as a margin of error, and many do not use the absent yolk sac as a sign of pregnancy failure. This is partly due to interobserver variability in measurements. Given these variables, the Society of Radiologists in Ultrasound recently advocated diagnosing early pregnancy failure by gestational sac size only for sacs with MSD of 25 mm or greater with no embryo ( Fig. 30.20 ).

FIG. 30.20, TVS Findings Diagnostic of Early Pregnancy Failure With Large, Empty Sac.

Furthermore, these parameters only apply to high-resolution TVS and cannot be used for examinations performed with a 5-MHz TVS probe. Rowling et al. studied early pregnancies with lower-frequency TVS probes (5 MHz) as well as higher-frequency probes (9-5 MHz broadband). The gestational sac was first seen at 6.4 mm in size with the lower frequency but at 4.6 mm with higher frequencies. A yolk sac was always seen in normal pregnancies with a gestational sac greater than 5 mm, and an embryo was always seen with a sac of 13 mm, using frequencies above 5 MHz.

Worrisome Findings of Early Pregnancy Failure

Additional sonographic features may suggest an abnormal outcome but lack the specificity in isolation to diagnose early pregnancy failure. These include findings involving the gestational sac, yolk sac, amnion, yolk sac, and embryo ( Table 30.2 ).

TABLE 30.2

Worrisome Findings for Early Pregnancy Failure

Finding	Comment
Embryo with CRL < 7 mm and no heartbeat	Embryo 2-6 mm without cardiac activity is a worrisome finding. Follow-up is needed to assess for cardiac activity in 1 week to ensure 100% specificity in diagnosis of miscarriage.
Gestational sac with MSD 16-24 mm and no embryo	Embryo is typically seen by the time the MSD is 16 mm. Follow-up in 10-14 days is needed to ensure 100% specificity in diagnosis of miscarriage.
Gestational sac appearance	Irregular shape of sac, low position of sac, and weak decidual reaction are associated with miscarriage, but the size of the embryo and presence or absence of cardiac activity guides the diagnosis of miscarriage.
Small MSD in relationship to CRL	Low fluid is associated with poor outcome. If MSD-CRL < 5, follow-up is recommended.
Abnormal amnion size	Expanded amnion or empty amnion as evaluated by an experienced sonologist is diagnostic of miscarriage. If any uncertainty is present, then follow-up should be obtained.
Yolk sac > 6 mm Calcified yolk sac	Findings are associated with miscarriage, but the size of the embryo and presence or absence of cardiac activity guides the diagnosis.
Embryonic bradycardia	Heart rate (HR) < 100 may be seen with 1- to 2-mm embryo and be a normal finding. In general, when HR is <100, follow-up is recommended.
Large subchorionic hemorrhage	Large hemorrhage is associated with miscarriage, but the size of the embryo and presence or absence of cardiac activity guides the diagnosis of miscarriage.

Embryos With Crown-Rump Length Less Than 7 mm and No Heartbeat

If on initial imaging, an embryo is seen measuring less than 7 mm and lacking cardiac activity, the findings are worrisome but not entirely diagnostic of early pregnancy failure. As previously stated, findings on ultrasound follow a typical pattern with an embryo with a heartbeat demonstrable at 6 weeks. Small embryos usually demonstrate measurable cardiac activity, but lack of a heartbeat in a small embryo of less than 7 mm may still result in a normal pregnancy. Follow-up sonography should be performed in these cases. Given the reliable pattern of growth, early pregnancy failure can also be verified on ultrasound by lack of visualization of an embryo with cardiac activity on follow-up scans. Embryonic cardiac activity should be documented by 11 days after a scan demonstrating a gestational sac with a yolk sac or by 14 days after a scan demonstrating a gestational sac without a yolk sac. If the pregnancy does not meet these milestones in this time interval, early pregnancy failure can be reliably diagnosed.

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