Ultrasound for Congenital Fetal Anomalies Sonal Panchal
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Normal and Abnormal EmbryoCHAPTER 1

Chaitanya Nagori
Sonal Panchal
 
INTRODUCTION
The earliest phase of human life is the embryo and the fetus from fertilization till the end of the first trimester. This is a highly dynamic phase consisting of several developmental and evolutionary processes. This complex process was earlier studied only by observing the lab specimens of aborted fetuses. Development of high resolution transvaginal ultrasound especially with volume scan technology has brought a revolution in the study of embryo.
These scans are done with intracavitary (transvaginal) probes with frequencies varying from 5–12 MHz.
Early pregnancy can be assessed even before the sac appears. It is known that the blastocyst implants in the endometrium, five days after the fertilization of the ovum in the fallopian tube, i.e. approximately 18th to 20th day of the 28 days cycle. With implantation the progesterone secretion is enhanced from corpus luteum and this is reflected as increased blood flow to the corpus luteum. The receptive organ to this progesterone and proteolytic and other factors is the endometrium. It thickens due to the decidual reaction. New blood vessels develop to provide nutritional support to the embryo.
On ultrasound these changes are represented as:
  • 2D US
    • Asymmetrical endometrial thickening. (one of the endometrial is more thickened as compared to other because of implanting embryo
    • Corpus luteum (Figure 1).
  • Color Doppler
    • Corpus luteum vascularity with low RI <0.5 (Figure 2A).
    • High velocity, low resistance trophoblastic flow (PSV >6) in the thickened endometrial lip. This is typically described as a comet sign by Honemeyer et al. (Figure 2B).1
  • 3D US
    • Asymmetrical endometrial thickening is more evident on 3D US, with thickened part showing increase echogenecity due to decidual reaction and increased vascularity (Figure 3).
Endometrial thickness of <6 mm, nonhyperechogenic endometrium with scanty vascularity in midluteal phase are negative predictors of conception.
Embryo is a very fast growing structure and therefore its anatomy changes every day or may be even faster.
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Figure 1: Corpus luteum and asymmetrical endometrium on B-mode (brightness mode)
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Figure 2: Corpus luteum and comet sign in endometrium
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Figure 3: 3D US: Possibly conception cycle: midluteal phase
It is understood that scans can not be done or findings cannot be described so often. Therefore changes in the embryo are described week to week.
Scans are done during early pregnancy for:
  • Confirmation of pregnancy
  • Confirm location of pregnancy
  • Early detection of multiple gestation
  • Assessment of progress of pregnancy
  • Evaluation of abnormal early pregnancy.
 
CONFIRMATION OF PREGNANCY
Presence of gestational sac can be confirmed in the endometrial cavity as early as four weeks and 3–4 days by transvaginal scan and is diagnostic of pregnancy. Gestational sac is a round/oval anechoic structure with thick hyperechoic margins eccentrically placed in the endometrium (Figure 4).
This echogenic margin is because of decidual reaction and is known as double decidual ring sign.
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Figure 4: True gestational sac
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Figure 5: Pseudo sac
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Figure 6: Residual endometrial cavity
Table 1   Difference between true sac and pseudosac
Features
True sac
Pseudosac
Situation
Eccentric in endocavity
Central in endocavity
Margins
Double decidual ring
No hyperechoic ring
With uterine peristalsis
No change in shape
Changes shape
On Doppler
Peripheral vascular ring
No peripheral vascularity
The true gestational sac must be differentiated from pseudosac (Figure 5), that may often be seen in patients with ectopic pregnancies and the differentiating points are given in Table 1.
β hCG is the earliest and the first marker for confirmation of pregnancy and gestational sac must be detected in the endometrial cavity on transvaginal scan when β hCG levels are >1000 IU/mL. In absence of which, an abnormal pregnancy must be suspected. At appearance, gestational sac is 2–3 mm in diameter. It grows at the rate of 1 mm/day and at 7 weeks it occupies 1/3rd of endometrial cavity. As it is implanted in one of the endometrial leaves, the endometrial cavity still persists till the sac grows large enough to abut the cavity. This residual cavity may be seen till 7 weeks and fluid seen surrounding the sac till this time should be first considered as a residual cavity, rather than perisac bleeding (Figure 6).
A gestational sac that is not circular, does not have thick echogenic margins, appears late and does not show peripheral vascularity, is considered abnormal and carries a bad prognosis for pregnancy (Figure 7). Choirionic thickness of atleast 3 mm is considered a sign of healthy pregnancy.
 
CONFIRM LOCATION OF GESTATIONAL SAC
Normally, the gestational sac is implanted in the fundal area (Figure 8). Gestational sac that is implanted at any other location, is considered abnormal or ectopic.
Gestational sac that is implanted low (Figure 9) in the endometrial cavity, though may not be called ectopic but has increased chance of abortion.
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Figure 7: Irregular gestational sac and a large gestational sac
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Figure 8: Normally implanted gestational sac
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Figure 9: Low implanted sac in a twin pregnancy
Other locations of gestational sac in uterine cavity that are not considered normal are angular and interstitial pregnancy. Gestational sac in angle usually cannot grow beyond 8 weeks and can lead to serious complications. Interstitial part of the tube is covered by myometrium and cannot distend beyond 6–7 weeks. Differentiation between two is also important.
In interstitial pregnancy, sac is seen >1 cm lateral from the lateral edge of the endometrial cavity and is surrounded only by a thin layer of myometrium. Where as an angular pregnancy, medially is in continuity with the endometrium, but lateral to the gestational sac, no endometrial mantle is seen (Figure 10).
Gestational sac may also implant in the cervix and is known as cervical pregnancy and is typically seen as ballooning of the cervix and hour glass shape of the uterus (Figure 11).
Cervical pregnancy can be differentiated from abortion in process of abortion by its eccentric location in the cervical canal and surrounding vascularity. Rarely gestational sac may implant in a uterine scar of previous surgery also. This is known as a scar pregnancy. Scar pregnancies are more often seen now than earlier probably because of increased number of ceasarean pregnancies than earlier. These pregnancies typically do not show any endometrium surrounding the sac.
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Figure 10: Angular pregnancy and interstitial pregnancy
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Figure 11: Cervical pregnancy
Abnormal locations of pregnancy, that are extrauterine are in the tube, ovary or free in the peritoneal cavity. Tubal ectopics are the commonest of all ectopic pregnancies.
Typically presentation of a patient with ectopic pregnancy is a history of missed period with raised β-hCG levels, though lower than expected for the time of gestation with either fainting attacks, dizziness or acute lower abdominal pain. Some patients may also present with spotting.
The ultrasound diagnostic signs are:
  • Tubal ectopic
    • No intrauterine gestational sac with symmetrical endometrial cavity (Figure 12A)
    • Adnexal mass with peripheral low resistance vascularity with or without gestational sac, which is tender on probe pressure (Figure 12B)
    • Ipsilateral active corpus luteum
    • Free fluid in pelvis.
  • Ovarian ectopic (Figure 13)
    • No intrauterine gestational sac with symmetrical endometrial cavity
    • Anechoic circular gestational sac in ovary with typical hyperechoic decidual reaction like rim, with peripheral vascularity
    • This can be differentiated from a corpus luteum only by its hyperechoic rim
    • It must be remembered that ovarian ectopic pregnancies are extremely rare and are often over diagnosed.
  • Abdominal/peritoneal ectopic (Figure 14)
    • No intrauterine gestational sac with symmetrical endometrial cavity
    • Gestational sac is seen lying free outside uterus, tubes or ovaries
    • It is usually surrounded by fluid
    • Location of the gestational sac in these cases can not be related to ovaries or adnexa
    • Is very difficult to locate as it can be placed anywhere in the peritoneal cavity.
It must be remembered that ectopic pregnancy may coexist with intrauterine pregnancy and is known as heterotopic pregnancy.
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Figure 12: (A) Symmetrical endometrial cavity: Equal thickness of either endometrial leaf; (B and C) Tubal ectopic pregnancy
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Figure 13: Ovarian ectopic pregnancy
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Figure 14: Abdominal ectopic pregnancy
 
EARLY DETECTION OF MULTIPLE GESTATION
Multiple gestations have much higher complication rate than singleton pregnancy. The complication rate and management are different for monochorionic and dichorionic, and monoamniotic and diamniotic pregnancies. It is therefore essential to confirm the chorionicity and amnionicity of any multiple gestation. This can be best done at 6–8 weeks of pregnancy. 7This is the time when gestational sacs are small and therefore individual sac margins can be confidently identified (Figure 15). Without mentioning the chorionicity and amnionicity, no report of multiple gestation is to be considered complete.
 
GROWTH AND PROGRESS OF PREGNANCY
Growth of pregnancy is assessed by increase in the size of gestational sac or fetal pole and appearance of new structures. Gestational sac, yolk sac, amniotic sac and fetal pole, all have a definite time of appearance and pace of growth. These growth rates are very precise in first trimester and do not have genetic or individual variation. Abnormalities of these can be signs of abnormal prognosis of pregnancy. The technique for these measurements therefore should be standardized.
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Figure 15: Multiple gestations: Dichorionic diamniotic twins
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Figure 16: (A) Measuring gestational sac, yolk sac and CRL (crown rump length); (B) Sono AVC calculation gestational sac volume
 
Gestational Sac (Figure 16A)
  • Measured from inner edge to inner edge.
  • Always take a mean of three orthogonal diameters.
  • Volume is now considered more reliable
  • Gestational sac volume can be assessed best by 3D ultrasound and VOCAL/Sono AVC (automated volume calculation) software and is especially required when the gestational sac is not round (Figure 16B).
Yolk sac appears toward the end of the fourth week or when gestational sac is 10 mm in diameter. Fetal pole must be seen when gestational sac is 15 mm in diameter.
 
Yolk Sac
It has nutritive, metabolic, endocrine, immunological and hematopoietic functions. 8It must be seen after 7–8 days of visualization of the gestational sac. It is a confirmatory sign of true gestational sac.
  • Measured inner wall to inner wall
  • Increases 0.1 mm/day till 10 weeks—max. 5–6 mm.
Yolk sac is an indicator of poor outcome of pregnancy if it is (Figure 17)
  • Too small yolk sac <2 mm
  • Too large yolk sac >6 mm
  • Thick walled yolk sac
  • Irregular yolk sac
  • Solid yolk sac.
It was only 3D ultrasound which made possible to see the yolk sac surface and recognized it as a structure having honeycomb surface instead of a smooth one (Figure 18).
Yolk sac volume by 3D US along with its vascularity have been found to be predictive of pregnancy outcome by Kupesic et al.2
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Figure 17: Solid, large, thick walled and irregular yolksac (clockwise)
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Figure 18: Progressive changes in yolk sac as embryo develops
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Figure 19: Measuring crown rump length
 
Fetal Pole
Fetal pole is the structure to follow the appearance of yolk sac. Detection of the fetal pole is actually by visualization of the cardiac activity. By transvaginal ultrasound fetal cardiac activity can be detected at 5–6 weeks approximately, when the fetal pole appears like a linear structure by the side of the yolk sac of approximately 1–2 mm in length. Its length is measured from end to end and grows at a rate of 1 mm/day. Size to date discrepancy of up to 5 days can be considered to be within normal limits. Difference in CRL of >7 mm of normal indicates three times higher risk of aneuploidy.
CRL is considered to be the most reliable measure parameter for assessment of the fetal age. It is a reliable parameter till 10–11 weeks. Beyond this gestational age, the fetus has a tendency to flex on its trunk and so crown rump length can not be then considered a reliable parameter of assessment of gestational age. The gestational age is therefore decided based on CRL in the first trimester and it must be remembered that the gestational age once decided in the first trimester, it should then not be changed. This is of special importance when the patient is not sure of dates or when IUGR is suspected in the later trimesters.
Being of such importance therefore CRL must be measured with due standardization. When the fetus is not flexed, in the mid-sagittal section and end to end. Midsagittal section is confirmed by absence of visualization of any of the fetal lower limbs in the image and if the upper limbs are seen these are only the distal part of the upper limbs which are usually in front of the fetal chest as this is a very common habitus of the fetus at this gestational age (Figure 19).
 
10CARDIAC ACTIVITY
Cardiac activity must always be seen at all times after 6 weeks of pregnancy. Appearance of a fetal pole, without cardiac activity is a sign of abnormal (nonviable) pregnancy.
 
Normal Heart Rate
  • 5th week—slow like peristalsis—60–80/min
  • End of 5th week—100/min
  • End of 6th week—105–130/min
  • 9 weeks—160–170 / min, then 120–160/min
  • Heart rate of >200/min is termed as tachycardia and <100/min is termed as bradycardia in the first trimester, though it is known that in the later pregnancy this limit is 120–160 bpm.
Persistently abnormal heart rate has a bad prognosis and late appearance of cardiac activity also indicates pregnancy with bad prognosis. Irregular cardiac rhythm is also a sign of cardiac arrhythmia and high risk of cardiac abnormalities but is more evident and considered of more importance in 2nd and 3rd trimesters of pregnancy.
3D power Doppler can be used to visualize the areas of developing intervillous circulation. 3D power Doppler allows to study the turgescent blood vessels withstanding from the surface of the yolk sac and also to study the evolution from embryovitelline to embryoplacental circulation. Study of both the intervillous and embryoplacental circulation can also be used prognostically to know the pregnancy outcome.
Structures then to appear by completion of each following week after 5 weeks are as follows:
 
SIX WEEKS (FIGURE 20)
Fetal pole with cephalic and caudal poles. Shape of the embryo now is a round bulky head and thin body, with no limb buds, but long omphalomesentric duct. Amniotic membrane is seen initially dorsally and then covering the embryo. Aortic and umbilical blood flows are now seen.
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Figure 20: Six weeks pregnancy
 
SEVEN WEEKS (FIGURE 21)
Spine and limb buds appear. Brain vesicles are now seen. Lateral ventricles appear like round vesicles and diencephalons (future third ventricle) runs posteriorly. Medial telencephalon forms a continuous cavity between two lateral ventricles. Foramen of Munro is wide and height of diencephalons is more than mesencephalon. Mesencephalic cavity, a tube like structure is future sylvian aqueduct, which lies aneriorly and points caudally. Two cerebral hemispheres can be identified. Early intracerebral circulation can also be seen by 3D power Doppler. Head is flexed over the chest.
Chorion now start differentiating into Chorion leave and chorion frondosum. It is the chorion frundosum which will form the future placenta. Amniotic membrane is now is visible.
 
Amniotic Membrane
Seen when CRL is 5–7 mm.
In early pregnancy, when its size is equal to yolksac, it shows like double bleb sign. Amniotic sac grows at a rate of 1 mm/day and fuses with chorion at about 14 weeks.
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Figure 21: Seven weeks embryo showing rhombencephalon and limb buds
If it doesn't fuse it may suggest a higher risk of chromosomal abnormality.
Normal US at eight weeks of pregnancy is a positive prognostic sign for a normal pregnancy outcome.
 
EIGHT WEEKS (FIGURE 22)
The trunk of the fetus strainghtens. Limb buds are seen as elongated projections ending with thicker areas (future hands and feet). Movements of the limb buds can also be seen towards to end of 8th week. Head flexion decreases as the ventricular system of the brain expands. Future 4th ventricle can now be visualized. Brain structure can now be seen clearly.3 Two distinct hemispheres with deepening of the rhombencephalic cavity. It now takes a pyramid like shape with central deepening of pontine flexures as peak of the pyramid.4
3D power Doppler now allows visualization of entire fetal circulation, including cerebral circulation. Physiological umbilical hernia starts appearing towards the end of the week, but becomes visible on ultrasound only in the subsequent week of gestation.
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Figure 22: Eight weeks embryo
 
NINE WEEKS (FIGURE 23)
Spine can now be seen along its entire length and neck and coccygeal prominence become evident. Omphalocele is well seen at ninth week. Elbows and knees can be identified and feet approach the midline. Lateral ventricles enlarge. Thallamic growth narrows down the anterior part of the third ventricle. Beyond CRL of 25 mm, a gap is seen between rhombencephalon and mesencephalon, due to growing cerebellum. Diencephalon starts narrowing in its upper anterior part. On axial section, falx and choroid plexuses can be identified.
At this stage, 3D can fairly clearly show fetal facial images.5 3D power Doppler shows circle of Willis and choroids plexus vessels (See Figure 6). Cranial venous system also can now be identified. Umbilical cord circulation can be clearly demonstrated with both arterial and venous pulsations.
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Figure 23: Nine weeks embryo showing prosen-, mesen- and rhomben-cephalon, strainghtened trunk and developing limb buds
 
TEN WEEKS (FIGURE 24)
Facial details—nose, orbits, maxilla and mandible can be seen. Abdominal organs like stomach, kidneys and bladder can be identified. Three cerebral vesicles—rhombencephalon, mesencephalon and prosencephalon, which start becoming visible in 9th week are more evident now. Cerebellum can be identified in the axial section. Hands and feet are developed. Fingers and toes can be identified. The feet approach the midline. Ossification of spine starts.
Power Doppler may show aorta and carotids also.
 
ELEVEN WEEKS
Culvarial ossification starts. Choroid plexus and falx are seen and on axial plain gives a typical butterfly appearance. Spinal column is now clearly seen. Facial sturctures- nose, orbits and jaws are easily identified. Abdominal organs are clearly seen. Physiological omphalocoele disappears latest by 11 weeks and 4 days.
 
TWELVE WEEKS (FIGURE 25)
Detailed facial structure—nose, eyes, ears, lips, premature skull bones with sutures in between, details of abdominal organs, limbs including not only fingers and toes but individual phalanges and detailed cerebral and cerebellar anatomy can be seen. Four chamberd heart can be seen. 3D power Doppler demonstrates complete fetal vasculature.
 
THIRTEEN WEEKS
The face is well defined. Facial features can be identified. Each vertebrae and IV disc can be identified. Diaphragm can be clearly visualized along with all abdominal organs. Umbilical hernia has already disappeared by this gestational age. Four chamber heart, out flow tracts and three vessel view can be seen in at least 40–50% of fetuses on transvaginal scan.
There are abnormalities that can be suspected or even at times diagnosed early in the first trimester.
These include:
  • Acrania (Figure 26): Cranial vault ossification starts at 10 weeks and is complete by the end of 12th week. Acrania is lack of skull bone development. This leads to abnormal head shape as the developing brain tissue is directly exposed to amniotic fluid. This can be diagnosed as early as 10 weeks of gestation. Brain when exposed to amniotic fluid, it is destroyed and results in anencephaly.
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    Figure 24: 10 weeks pregnancy
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    Figure 25: Anatomical details of 12 weeks fetus
  • Encephalocele: This is deficient development of the neural tube posteriorly, leading to herniation of meninges and sometimes brain tissue also.
    Partial failure of closure of cephalic end of neural tube and lack of neurocranium results in exencephaly.
  • Holoprosencephaly (Figure 27): Cessation of cleavage of prosencephaly leads to holoprosencephaly, which may be lobar, semilobar or alobar depending on the stage of arrest. This results in absence of development of falx. It has been discussed earlier that falx can be seen at all times after completion of 9th week. If it is not seen beyond 10th week, holoprosencephaly must be suspected. Apart from fused thalami and basal ganglia there are several facial defects like cleft lip, palate, hypotelorism, cyclopia, arhinia with proboscis associated especially with alobar holoprosencephaly.
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    Figure 26: Acrania-irregular head shape due to absence of culvarium
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    Figure 27: Holoprosencephaly
  • Iniencephaly: It is a persistent hyperextension habitus of the fetus, typically described as a star gazing fetus (Figure 28).
  • Major limb abnormalities (Figure 29): All limb buds appear at 8 weeks and by the end of 10 weeks, all the segments of all four limbs are formed. Complete or partial absence of any of the limbs can be detected at all times after 10 weeks. Severe limb abnormalities like phocomelia, sirenomelia, and even club foot can be diagnosed as early as 12 weeks of pregnancy. Bone dysplasias like achondroplasia can be also diagnosed by 12 weeks but are better demonstrated with 3D ultrasound as it shows the entire fetus in a single image and therefore the disproportion is easy to demonstrate.
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    Figure 28: Iniencephaly
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    Figure 29: Major limb abnormalities
  • Situs abnormalites: Situs inversus is complete reverse position of all fetal organs: a mirror image, where heart, aorta and stomach are on right side and liver, gall bladder and IVC are on left side. Situs solitus with dextrocarida is when the abdominal organs and the aorta have a normal position but the heart is on the left side. Situs inversus with levocardia, when all abdominal organs and aorta are on opposite side than what they should be in but the heart is in the normal position on left side. As heart and stomach are developed and are evident at 10 weeks, their position can be checked and situs abnormalities can be diagnosed in first trimester.
  • 16Major cardiac abnormalities: By 11 weeks, four chamber heart is formed and can be seen clearly on transvaginal scan. Major cardiac abnormalities like single ventricle, truncus arteriosus, etc. can be diagnosed on first trimester scans.
  • Major spinal defects: Ossification centers of the spine are formed at the end of 10 weeks. Major spinal defects, multiple vertebral abnormalities, hemivertebrae, etc. can be diagnosed on first trimester scans.
  • Facial anomalies: Maxilla and palate can be reliably studied as early as 11 weeks by axial section as well as coronal section (premaxillary triangle) (Figure 30).
    Early diagnosis of median cleft syndrome is possible in which the frontal bones and nasal bones are largely separated with hypertelorism, flat nasal bridge, rudimentary nostrils and other facial abnormalities.6 Palate can be best studied by TUI of face in transverse section in first trimester, though later in pregnancy rendering may be more helpful. Lips may be better visualized in anterior coronal sections and rendered image. Abnormalities like facial cleft, micrognathia, nasal abnormalities and eye abnormalities like anophthalmia, can all be seen by 3D ultrasound, as early as late first trimester. Genetic syndromes are often diagnosed by craniofacial dysmorphism.
  • Abdominal wall defects: Herniation of the bowel loops through the anterior abdominal wall at the base of the umbilical cord—omphalocele is a physiological phenomenon from 9th to 11th week. Even during that period a omphalocele neck of larger than 7 mm or an omphalocoele that is larger than the actual fetal abdominal circumference is pathological. This size assessment is more precise by 3D ultrasound rather than 2D US (Figure 31). An omphalocele which projects beyond 11 weeks, may contain liver or bowel and depending on this content the fetus may have a lower or higher risk of chromosomal abnormality respectively. This differentiation is easy by Doppler, depending on hepatic vessels are seen in the abdomen or in the omphalocele. Gastroschisis is another abdominal wall defect which has attachment of the umbilical cord by the side of the defect in abdominal wall.
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    Figure 30: Normal premaxillary triangle
  • Chorioangioma (Figure 32): Chorioangioma is an overgrowth, tumor of the chorionic tissue. These can be seen very early in pregnancy, 7–8 weeks of pregnancy. Small chorioangiomas do not affect the pregnancy, but larger ones may lead to circulatory failures in fetus.
  • Vesicular mole (Figure 33): Another chorionic lesion, vesicular mole is a common lesion. High β-hCG levels with absent gestational sac with thick echogenic endometrium, that has small anechoic areas is diagnostic of vesicular mole. In early phases, vascularity may not be picked up on Doppler studies due to low velocity flow. Only when it becomes invasive, it disrupts the endometriomyometrial junction and then is usually large enough to show abundant low resistance vascularity.
  • Miscellaneous abnormalities: Umbilical cord cyst is another not so uncommon lesion, that can be picked up in first trimester, but is not clinically significant (Figure 34).
    Single umbilical artery is also now not given significant clinical importance.
    Amniotic bands also can be picked up by the end of the first trimester.
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    Figure 31: Omphalocele and gastroschisis
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    Figure 32: Chorioangioma
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    Figure 33: Vesicular mole
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    Figure 34: Umbilical cord cyst
    These may at times lead to amputation like major consequences in later pregnancy, often times these may not be of any significance.
    Of course ultrasound plays a major role for diagnosis of chromosomal abnormalities in the first trimester. The dedicated scan is known as a nuchal scan or a genetic scan or 11–13+6 weeks scan, but that will be discussed in chapter 3.
    Detailed and careful systematic scanning technique can therefore help in early diagnosis of several fetal abnormalities. Volume ultrasound is very informative for first trimester scanning.
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