Course Advanced learning material about the challenges of human reproductive medicine in a changing Europe for OB/GYN residents

Challenges of the ultrasound examinations during pregnancy (Advanced level)

There are several techniques aimed to visualize the developing fetus in utero. Among the currently available techniques the use of methods utilizing ionizing radiation are limited, due to their known mutagenic and teratogenic effects. CT scans or X-rays should only be used after individual assessment considering the risk and the benefit for the patient and the fetus. MRI scans provide the best quality images, and they might overcome their limitations in the near future. Dense bony structures, such as the skull and the rib cage can be examined precisely, and it is not even influenced by the fetal lie, or position. Although this method also have limitations: motion artifacts originate from fetal movement can cause problems during image acquiring, and the method itself is expensive, and there is a few radiologists familiar with embryology and developmental anomalies.

Since the 1980s-1990s the gold standard of fetal imaging is the ultrasound (US). But how does it work?

It is based on the Piezzo-electric principle. The probe contains crystals, which under electrical current start to shake on top of each other, generating and emitting sound waves. The soundwaves are over the range what the human ear can detect, that’s why it is called ultrasound. Since air is a poor conductor of the ultrasound waves a coupling gel must be applied between the skin of the patient and the probe. Once the soundwaves are penetrated the patient, they are either absorbed, or emitted. This is depending on the water content of the organs scanned, because water allows the soundwaves to pass through, while other organs reflect the US (echo). If reflection happens, the soundwaves undergo change in frequency, which returns to the probe and the machine pick it up and matches it with a color on a 2-dimensional greyscale image. High US reflecting organs (like the bones) are hyperechoic, and will appear white on the screen, in the contrary hypoechoic organs (amniotic fluid, urine, etc) will be seen as black. All other organs depending on their reflection abilities will appear on the shades of grey on the monitor.

How do you diagnose pregnancy?

Pregnancy is diagnosed with US scan, not earlier than 6. weeks (calculated from the last menstrual period-LMP), during which viable (heartbeat) in utero embryo needs to be seen through a vaginal scan. If the LMP is not clear enough, the gestational age can be determined through the measurement of the crown-rump-length (CRL) of the fetus, which is the distance between the top of the head and the lowest point of the buttocks in millimeters.

What is the difference between screening and diagnostic US examinations?

There is a cardinal difference between these two examination types. Screening US examination of a population contributes the unselected examination those, who does not have any symptoms or complains, it is an examination without sorting, with a goal to evaluate pathological conditions from normal by screening the whole population. On the other hand, diagnostic examination is a process of detailed evaluation of a special population, who has abnormal blood test results, positive medical history, abnormal ultrasound findings, with a goal to confirm major and minor congenital anomalies. Although there are three planed US screenings (first trimester scan between week 11-13; second trimester scan between week 18-22, and third trimester scan between week 28-32) nowadays the most important scan is the first trimester scan. The following link contains the guideline of the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) according to who, how, and when should perform a first trimester US scan:
https://www.isuog.org/uploads/assets/uploaded/4daa1ea7-bc64-4c24-b81b17df5a684a38.pdf

What aspect should I focus on during a first trimester scan?

The fetal medicine foundation provides helpful hints and even a certification option for those who would like to carry out first trimester scans (https://fetalmedicine.org/).

1. Nuchal translucency scan: Nuchal translucency (NT) is the sonographic appearance of a collection of fluid under the skin behind the fetal neck in the first trimester of pregnancy. The term translucency is used, irrespective of whether it is septated or not and whether it is confined to the neck or envelopes the whole fetus. In fetuses with chromosomal abnormalities, cardiac defects, and many genetic syndromes the NT thickness is increased.

Screening by NT can detect about 80% of fetuses with trisomy 21 and other major aneuploides for a false positive rate of 5%. The combination of NT and maternal serum free β-hCG and PAPP-A improves the detection to 90%. There is now evidence that the detection rate can increase to about 95% and the false positive rate can be reduced to 3% by also examining the nasal bone, ductus venosus flow and tricuspid flow. For certification check: https://fetalmedicine.org/fmf-certification-2/nuchal-translucency-scan.

2. Preeclampsia screening: Preeclampsia (PE) is an important cause of maternal and perinatal mortality and morbidity. Consequently, a major challenge in modern obstetrics is early identification of pregnancies at high-risk of preterm PE and undertaking of the necessary measures to improve placentation and reduce the prevalence of the disease. There is now evidence that a combination of maternal demographic characteristics, including medical and obstetric history, uterine artery pulsatility index (PI), mean arterial pressure (MAP) and placental growth factor (PlGF) at 11-13 weeks' gestation can identify a high proportion of pregnancies at high-risk for preterm PE. Such early identification of the high-risk group for preterm PE is important because the risk is substantially reduced by the prophylactic use of low-dose aspirin starting from 11-13 weeks. For certification check:
https://fetalmedicine.org/fmf-certification-2/preeclampsia-screening-1

3. Nasal bone: In a high proportion of fetuses with trisomy 21 and other chromosomal abnormalities the nasal bone is hypoplastic or not visible at 11-13 weeks' gestation. Assessment of the nasal bone at 11-13 weeks improves the performance of combined screening for trisomy 21 by maternal age, fetal nuchal translucency (NT) and serum biochemistry. The difficulty is when the gestation is 11 weeks or the beginning of the 12th week and the nasal bone is absent but the NT, the other ultrasound markers and the serum biochemistry are normal. Our advice is that in such cases the scan should be repeated in one week and if there is persistence of absence of the nasal bone then the risk for trisomies is increased. For certification check:
https://fetalmedicine.org/fmf-certification-2/nasal-bone

4. Ductus venosus flow: Increased impedance to flow in the fetal ductus venosus at 11-13 weeks’ gestation, is associated fetal aneuploidies, cardiac defects and other adverse pregnancy outcomes. Most studies examining ductus venosus flow have classified the waveforms as normal, when the a-wave observed during atrial contraction is positive, or abnormal, when the a-wave is absent or reversed. The preferred alternative in the estimation of patient-specific risks for pregnancy complications is measurement of the pulsatility index for veins (PIV) as a continuous variable.
Inclusion of ductus venosus blood flow in first-trimester combined screening improves the detection rate for trisomy 21 from about 90% to 95% for a false positive rate of 3%. Assessment of ductus venosus flow need not be carried out in all pregnancies undergoing routine first-trimester combined screening. Such examination could be reserved for the 15% of the total population with an intermediate risk (between 1 in 51 and 1 in 1000) after combined testing. For certification check:
https://fetalmedicine.org/fmf-certification-2/ductus-venosus-flow

5. Tricuspid flow: Tricuspid regurgitation at 11-13 weeks’ gestation is a common finding in fetuses with trisomies 21, 18 and 13 and in those with major cardiac defects. Tricuspid regurgitation is found in about 1% of euploid fetuses, in 55% of fetuses with trisomy 21 and in one third of fetuses with trisomy 18 and trisomy 13. Inclusion of tricuspid blood flow in first-trimester combined screening improves the detection rate for trisomy 21 from about 90% to 95% for a false positive rate of 3%. Assessment of tricuspid flow need not be carried out in all pregnancies undergoing routine first-trimester combined screening. Such examination could be reserved for the 15% of the total population with an intermediate risk (between 1 in 51 and 1 in 1000) after combined testing. For certification check:
https://fetalmedicine.org/fmf-certification-2/tricuspid-flow

How to assess the growth and development of the fetus in utero?

The assessment of the fetus can be achieved through the establishment of the biophysical profile, containing four measurements (biparietal diameter – BPD; head circumference – HC; abdominal circumference – AC; femoral length – FL). Comparing the measured values into a preset database (Headlock, etc.) the machine calculates a gestation age, which can be compared with the gestational age determined by the LMP. The estimated birth weight is distributed according to a Gauss curve. Fetuses under the 10-percentile range are considered small for gestational age (intra uterine growth restricted), while fetuses over the 90-percentile range are called large for gestational age (macrosomia).

SGA can be, due to genetic predisposition (short parents), or developmental disturbance called intrauterine growth restricted (IUGR). There are two forms of IUGR, the early onset type (symmetrical) is caused by genetic anomalies, the other type is late onset form (asymmetric), often caused by placental insufficiency.

The main factors of IUGR are listed above:

Maternal factors:
-High blood pressure
-Chronic kidney disease
-Advanced diabetes
-Heart or respiratory disease
-Malnutrition, anemia
-Substance use (alcohol, drugs)
-Cigarette smoking

Factors involving the uterus and placenta:
-Decreased blood flow in the uterus and placenta
-Placental abruption (placenta detaches from the uterus)
-Placenta previa (placenta attaches low in the uterus)
-Infection in the tissues around the fetus

Factors related to the developing baby (fetus):
-Multiple gestation (for example, twins or triplets)
-Infection
-Birth defects
-Chromosomal abnormality

LGA is also multifactorial, but most of all maternal diabetes is the main reason for it. Fetal hyperinsulinemia, as a response to high maternal glucose levels which bypasses the placenta, triggers the attachment of insulin molecules into the insulin-like growth factor receptors. Macrosomia can result dystocia during labor, therefore need to be diagnosed with US before delivery.

How can we determine the amniotic fluid?

Amniotic fluid is vital to the well-being of the fetus. It cushions the fetus from injury, helps prevent compression of the umbilical cord, and allows room for it to move and grow. In addition, its bacteriostatic action helps prevent infection of the intra-amniotic environment. The quantity of amniotic fluid at any time in gestation is the product of water exchange between the mother, fetus, and placenta, and is maintained within a relatively narrow range. Disorders of this regulatory process can lead to either polyhydramnios or oligohydramnios, in which too much or too little fluid exists, respectively. These disorders may result from abnormal fetal or maternal conditions and, conversely, may be responsible for alterations of fetal well-being as well. With the advent of real-time ultrasonography, assessment of amniotic fluid has been possible, resulting in earlier recognition of abnormal conditions and possible intervention. Because precise quantification of amniotic fluid volume is not possible with ultrasonography, various techniques for both qualitative and semiquantitative assessment have been proposed. The amount of the amniotic fluid can be objectively described by the determination of the amniotic fluid index (AFI). There are two techniques described in the lecture, how to measure the amount of the amniotic fluid with US.

Chronic and/or intermittent fetal hypoxemia
-Fetal growth restriction
-Postterm pregnancy
-Repetitive cord compression
-Fetal anomalies
-Renal agenesis
-Renal anomalies (e.g., multicystic dysplastic kidneys, polycystic kidneys)
-Posterior urethral valves
-Bilateral ureteropelvic junction obstruction
-Non-steroidal anti-inflammatory medications
-Twin-to-twin transfusion
-Premature rupture of membranes

Reasons for Polyhydramnios:
(https://www.glowm.com/section-view/heading/Amniotic%20Fluid:%20Physiology%20and%20Assessment/item/208#)

Maternal conditions         Isoimmunization, Diabetes mellitus

Placental conditions        Chorioangioma ,Circumvallate placenta

Fetal conditions               Twin-to-twin transfusion syndrome
GI:                                  Esophageal atresia, duodenal or jejunal atresia, annular pancreas, midgut volvulus, diaphragmatic hernia, omphalocele, gastroschisis
CNS:                                 Anencephaly, hydrocephalus, encephalocele, spina bifida, microcephaly, hydranencephaly
Skeletal malformations:    Arthrogryposis multiplex, osteogenesis imperfecta, thanatophoric dysplasia
Fetal tumors:                    Cystic adenomatoid malformation of the lung, sacrococcygeal teratoma, cervical teratoma
Cardiac malformations:    Severe congenital heart disease, fetal arrhythmias
Genetic disorders:          Down syndrome, trisomy 13 and 18, Pena-Shokeir syndrome, multiple congenital anomalies, myotonia dystrophica
Hematologic disorders:     Homozygous α-thalassemia, fetomaternal hemorrhage
Intrauterine infections:       Rubella, syphilis, toxoplasmosis, parvovirus
Miscellaneous:                   Nonimmune hydrops fetalis, fetal retroperitoneal fibrosis

How to assess the fetal circulation and the fetal wellbeing?

By definition, the Doppler effect refers to the change in wave frequency during the relative motion between a wave source and its observer, and it allows us to assess the blood flow inside the fetal vessels.

The fetal circulatory system uses 3 shunts. These are small passages that direct blood that needs to be oxygenated. The purpose of these shunts is to bypass the lungs and liver. That's because these organs will not work fully until after birth. The shunt that bypasses the lungs is called the foramen ovale. This shunt moves blood from the right atrium of the heart to the left atrium. The ductus arteriosus moves blood from the pulmonary artery to the aorta.
Oxygen and nutrients from the mother's blood are sent across the placenta to the fetus. The enriched blood flows through the umbilical cord to the liver and splits into 3 branches. The blood then reaches the inferior vena cava. This is a major vein connected to the heart. Most of this blood is sent through the ductus venosus. This is also a shunt that lets highly oxygenated blood bypass the liver to the inferior vena cava and then to the right atrium of the heart. A small amount of this blood goes straight to the liver to give it the oxygen and nutrients it needs. Waste products from the fetal blood are transferred back across the placenta to the mother's blood.
(https://www.stanfordchildrens.org/en/topic/default?id=fetal-circulation-90-P01790)

During hypoxia there is redistribution in the fetal circulation resulting centralized circulation, also called brain-sparring effect. During this condition blood flow in favor of the brain, heart, and adrenals and at the expense of almost all peripheral organs, particularly of the lungs, carcass, skin and scalp. This leads to hypoxic vasodilatation in the fetal brain, which can be picked up by the assessment of the middle-cerebral artery peas systolic velocimetry, where we will find decreased resistance, and increased flow. The hypoxia also can be seen in the umbilical vessel flowmetry, where at the beginning end-diastoic stop, and later reverse flow can develop. The presence of absent end-diastolic flow (AEDF) usually occurs as a result of placental insufficiency. Flow in the umbilical artery should be in the forward direction in normal circumstances. If placental resistance increases, the diastolic flow may reduce, later becoming absent and finally reverses (https://radiopaedia.org/articles/absent-umbilical-arterial-end-diastolic-flow-2). Absent end diastolic flow velocity in the fetal umbilical artery or aorta has been associated with high mortality, increased risk of necrotising enterocolitis, and haemorrhage.

Conclusion:

As technology develops the use of ultrasound becomes more and more essential for the assessment of fetal development and wellbeing. Such advances allow us to detect and diagnose conditions earlier, most preferably during the first trimester, unlike before.