The New Genetics: Is Ultrasound Dead?

There are those who pretend that we do not need ultrasound anymore to detect fetal anomalies, “Just use maternal blood and with various forms of genetic testing and you will be able to detect the majority of fetal anomalies.”

Well, let me rebuke this insinuation.

3D ultrasound image of a fetus.
Acrania in a fetus at 11 weeks.

Genetics

There is no doubt that prenatal genetic testing has come a long way from using only maternal age to assume a risk of Down syndrome (for instance 1 in 1250 at age 25 and 1 in 385 at age 35). Maternal serum screening came next. At first, levels of alpha-feto-protein (AFP) were found to be lower in mothers carrying fetuses affected with Down syndrome.

Then, other markers, such as human chorionic gonadotropin (hCG), unconjugated estriol, and dimeric inhibin A, were determined to display characteristic patterns in pregnancies with Down syndrome, with the introduction of the double, triple, and quadruple screening in the second trimester. This moved to the first trimester, with incorporation of fetal nuchal translucency (NT), pregnancy-associated plasma protein A (PAPP-A), and the beta subunit of human chorionic gonadotropin (β-hCG). A high detection rate of 85–90% was attained for Down syndrome and 90–95% for trisomy 18, with a 5% false-positive.

A combination of both the first and second trimester was introduced, to further improve the detection rate and, at the same time, decrease the false-positive rate.  In some of these tests only serum fetal-placental protein markers were considered (integrated) and in others ultrasound findings (NT) and various serum markers were combined (integrated, sequential, and contingent).   

It is widely accepted that testing of the type used nowadays originated from a Lancet paper in 1997 by Lo and colleagues, describing circulating cell-free fetal DNA (ccffDNA) in the plasma of pregnant women. It took almost 15 years for the technology to become clinically available1. At first, it was used to determine the risk of trisomies and sex chromosome anomalies. Originally designed as noninvasive prenatal diagnosis (NIPD) or noninvasive prenatal testing (NIPT), the general opinion is that these are still screening (and not diagnostic) tests, hence the designation noninvasive prenatal screening (NIPS). I prefer noninvasive DNA screening (NIDS) because, after all, ultrasound is NIPT!

Nowadays, NIDS can be used to identify Rhesus group and some single-gene fetal conditions, autosomal dominant, recessive or sex-linked (eg, cystic fibrosis, achondroplasia, thanatophoric dysplasia, sickle cell disorder, congenital adrenal hyperplasia, spinal muscular atrophy, and hemophilia). Most conditions require using a maternal blood sample only but many require a paternal blood sample. Normal karyotype doesn’t mean everything is fine, hence chromosomal microarray, introduced in the prenatal diagnosis clinical setting in 2005. Looking for submicroscopic aberrations <5Mb can provide additional diagnostics in about 10% of fetuses with multiple anomalies1. The latest reiteration of the technology is genome-wide monogenic NIDS2.

Screening beyond the common trisomies is currently not recommended by the American College of Obstetricians and Gynecologists3. So where does ultrasound stand?

Ultrasound is alive and doing fine, thank you

In the general population, chromosomal abnormalities are less frequent than structural abnormalities. A large number of fetal structural abnormalities, especially many lethal ones, can be diagnosed in the first trimester of pregnancy, therefore, ultrasound remains an essential part of the story. Ultrasound diagnosis of fetal anomalies has now moved from the mid-second trimester (18–22 weeks) to the late first–early second-trimester (approximately 11–14 weeks). It should be noted that a repeat scan at the “classical” time (18–22 weeks) is still recommended by most.

Ultrasound image of a fetus with the NT measurement marked.
Image courtesy of Sergiu Puiu, MD

Two major reasons for the early scan: it’s a perfect time to perform a nuchal translucency (NT) measurement and, at that stage, most structural anomalies that are already present are detectable. A few examples of what is observable include all 4 limbs and all digits, cranial anatomy, estimation of the cardiac axis, and omphalocele (which is associated with Beckwith-Wiedemann and CHARGE syndromes, limb-body stalk anomaly, and Pentalogy of Cantrell, to name a few). Amputations or other unusual cleft due to amniotic band syndrome are visible and cardiac position and orientation can also be determined. In incidences of heart defects, dextrocardia is associated with 90% and situs inversus with levocardia with over 95%.

Most of the above anomalies will be associated with an increased NT, as will pulmonary, gastrointestinal and genitourinary conditions, diaphragmatic hernia, skeletal dysplasia, fetal anemia, and abnormal lymphatic drainage4. A third of congenital abnormalities occurring in fetuses with increased NT may remain undetected in the first trimester of pregnancy, unless cfDNA is used in combination with fetal sonographic NT assessment. When karyotype is normal, 10% of fetuses with an increased NT (>95th percentile) have structural abnormalities5.

In one study5, 65% of structural abnormalities would have potentially been missed in the first trimester if cfDNA had been used as a first-trimester screening test without an early ultrasound scan. Furthermore, if cfDNA only was used, besides structural defects, one third of other anomalies would have been missed: sex chromosome abnormalities, triploidy, single gene disorders, and submicroscopic aberrations <5Mb. In addition to NT measurements and detection of structural anomalies, several other sonographic markers have been described: nasal bone, ductus venosus Doppler anomalies and tricuspid regurgitation, helping to determine a high-risk group for whom genetic screening will have a high yield.

When these or/and other ultrasound-diagnosed fetal anomalies are present, whole-exome-sequencing can add relevant information in cases when an etiology could not be elucidated by fetal karyotype testing or chromosomal microarray6.

In a very recent article, Bedei et al. propose several conclusions, one of them being: “NIPT should always be combined with a skilled ultrasound examination.”7

My thoughts, exactly8.

I purposely do not wish to initiate a discussion on the ethical, moral, philosophical, religious, or emotional values or demerits of prenatal diagnosis. While some will say that all this is a veiled “search and destroy” exercise, others will explain that knowledge is power. Power to choose but also power to be ready when the baby is born or power to correct certain anomalies in the womb or intervene immediately at birth. Both sides of this argument may be defensible, but that is for another blog.

References

1. Talkowski ME, Rehm HL. Introduction of genomics into prenatal diagnostics. Lancet 2019 Feb 23; 393(10173):719–721.

2. Rabinowitz T, Shomron N. Genome-wide noninvasive prenatal diagnosis of monogenic disorders: Current and future trends. Comput Struct Biotechnol J 2020; 18:2463–2470.

3. American College of Obstetricians and Gynecologists screening for fetal chromosomal abnormalities: ACOG practice bulletin summary, number 226. Obstet Gynecol 2020; 136:859–867.

4.  Baer RJ, Norton ME, Shaw GM, et al. Risk of selected structural abnormalities in infants after increased nuchal translucency measurement. Am J Obstet Gynecol 2014; 211:675.e1–19.

5. Bardi F, Bosschieter P, Verheij J, et al. Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening? Prenat Diagn 2020; 40:197–205.

6. Petrovski S, Aggarwal V, Giordano JL, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet 2019;393(10173):758-767

7. Bedei I, Wolter A, Weber A, Signore F, Axt-Fliedner R. Chances and challenges of new genetic screening technologies (NIPT) in prenatal medicine from a clinical perspective: A narrative review. Genes (Basel) 2021; 12:501. 8. Rauch KM, Hicks MA, Adekola H, Abramowicz JS. Aneuploidy screening: the changing role of ultrasound. In: Abramowicz JS (ed). Ultrasound in the First Trimester, a Comprehensive Guide. Switzerland: Springer International Publishing AG; 2016:131–152.

Jacques S. Abramowicz, MD, FACOG, FAIUM, is a professor of OB-GYN and Director of Ultrasound Quality Assurance in the Department of Obstetrics and Gynecology at the University of Chicago.

More from Jacques Abramowicz, MD:
COVID-19: How to Prepare Yourself and Your Ultrasound Equipment During the Pandemic, an on-demand webinar from the AIUM (a collaborative activity with Samsung).

Interested in learning more about obstetric ultrasound? Check out the following posts from the Scan:

Ultrasound Imaging of Obese Pregnant Women

As the rate of obesity continues to increase worldwide (last reported by the CDC as 42.4% as of 2017–2018), it has become even more evident that there is a great need to improve fetal cardiac visualization in obese pregnant women. Less than 50% of morbidly obese women have successful fetal 4-chamber and outflow tract visualization, compared to almost 90% of nonobese women.

Obese women are also significantly more likely than normal-weight women to have children with a congenital heart disease, with an even higher risk in morbidly obese women, who give birth to children who have higher odds of having atrial septal defects, hypoplastic left heart syndrome, aortic stenosis, pulmonic stenosis, and tetralogy of Fallot.

And when obese pregnant women have reduced rates of complete anatomic surveys, lower detection rates, and increased risk of fetal anomalies due to less than perfect anatomy visualization, how do we improve the fetal cardiac visualization?

A team of researchers from Eastern Virginia Medical School looked into whether ultrasound (US) imaging in early gestation could help.

Amara Majeed, MD; Alfred Abuhamad, MD; Letty Romary, MD; and Elena Sinkovskaya, MD, PhD, performed a study in which all study participants (obese pregnant women) with a gestational age of 13 weeks to 15 weeks 6 days, underwent an US exam using a transvaginal or transabdominal approach and color Doppler US for fetal cardiac screening, which they defined as complete when all components of the 4-chamber, right ventricular outflow tract, left ventricular outflow tract, and 3-vessel views were clearly visualized. The participants also underwent a traditional transabdominal examination at 20 to 22 weeks, and if that exam was incomplete, underwent another 2 to 4 weeks later.

What they found was that the addition of early-gestation US to the 20- to 22-week US exam of obese pregnant women substantially improved the visualization of fetal cardiac anatomy. And for the women with a BMI of greater than 40 kg/m2, the cardiac screening completion rate was even higher (significantly so) for the early-gestation exam plus a traditional exam (90%) than for the traditional exam plus the second traditional exam (72.7%).

Adding an ultrasound exam at a gestation age of 13 weeks to 15 weeks 6 days substantially improved the visualization of fetal cardiac anatomy, particularly for the women with a BMI of greater than 40 kg/m2. Having complete or more complete anatomy screening can enable an earlier, accurate diagnosis.

To read more about this study, download the Journal of Ultrasound in Medicine article, “Can Ultrasound in Early Gestation Improve Visualization of Fetal Cardiac Structures in Obese Pregnant Women?”. Members of the American Institute of Ultrasound in Medicine can access it for free. Join today!

If you have any questions about the study, please ask in the comments; the authors of the article will be happy to respond.

Point-of-Care Ultrasound for Pregnant Patients?

Point-of-care ultrasound, or POCUS, has become fully incorporated into almost every aspect of clinical care over the past 5 years. COVID-19 has further solidified the use of POCUS for the evaluation of dyspnea and cough given its portability. But what about the use of POCUS for a woman during pregnancy?

Ultrasound has been consistently employed to evaluate the fetus in all 3 trimesters. There is another patient, though; the mother! Rising maternal morbidity and mortality secondary to cardiovascular disease requires the obstetrical care provider to employ point-of-care clinical assessment that targets the maternal cardiovascular system.  This is the problem and the solution may be “getting a CLUE” by implementing cardiac limited ultrasound evaluation (CLUE) at the bedside as suggested by Kimura et al.

In contrast to fetal imaging, which utilizes higher frequency transabdominal and transvaginal ultrasound probes, penetration of the chest wall requires a lower frequency probe (2–4 mHz). Ideally, a low frequency probe that is compatible with most commonly used obstetrical equipment would facilitate ease of utilization. The CLUE protocol employs the following views: parasternal long axis view, lung anteroapex view, lung posterolateral base view, subcostal view, and right sub-xyphoid view. These views allow the clinician to evaluate the patient for pathophysiologic findings including the presence of pleural or pericardial effusion; abnormal contractility, chamber enlargement, and valvular dysfunction. Assessment of the size and collapsibility of the inferior vena cava can be a noninvasive marker of right-sided filling pressures to evaluate volume status in an oliguric patient with preeclampsia.

I propose that CLUE be extrapolated from the non-pregnant patient population for applicability in the pregnant patient population. This may be particularly relevant in certain scenarios including: triage of pregnant women with cardiac symptoms in an outpatient or in-patient setting as an adjunct to the physical exam; and labor and delivery units with lack, or limited immediate availability, of formal echocardiography. While anecdotal case experience suggest utility, formal studies designed to compare CLUE in pregnancy to the gold standard of transthoracic echocardiography will confirm the feasibility of CLUE in this unique population. Even though obstetricians are trained to perform obstetrical and gynecologic ultrasound, and are well versed with the existing ultrasound equipment on their units, additional training may be required. In addition to obstetrical care providers, other clinicians, such as emergency room and internal medicine providers, may also perform CLUE to assess the maternal cardiopulmonary system.

Limitations of point-of-care cardiac examination of the heart include both patient characteristics and technique. Large body mass size and enlarged breast tissue common in pregnancy can lead to imaging acquisition challenges. Off-axis imaging technique can lead to false positive or false negative diagnoses. Patient positioning should be optimized and shifted to left lateral tilt to accommodate aortocaval compression.

CLUE demonstrates potential as an innovative diagnostic point-of-care technique that can be adapted to maternal use. Timely future clinical studies that compare CLUE with formal echocardiography during pregnancy will further clarify its feasibility and full utility in the clinical arena as a tool to combat rising maternal morbidity in the new millennium.

  1. Kimura BJ, Shaw DJ, Amundson SA, Phan JN, Blanchard DG, DeMaria AN. Cardiac Limited Ultrasound Examination Techniques to Augment the Bedside Cardiac Physical Examination. J Ultrasound Med. 2015;34:1683–1690.

Carolyn M. Zelop, MD, is a Director of Perinatal Ultrasound and Research at The Valley Hospital, Ridgewood, New Jersey; a Clinical Professor of Ob/ Gyn at NYU School of Medicine; and she is a senior member of the AIUM and the ACOG rep to women’s imaging for ACR.

Interested in learning more about ultrasound and pregnancy? Check out the following posts from the Scan:

Saving Lives With Ultrasound: How to Improve Placenta Accreta Spectrum Antenatal Detection and Management

“You think of pregnancy as joy, laughter, preparation for a new life. Never did I think it was possible that I could risk losing my uterus or my life because of pregnancy.”

If I had a nickel for every time I heard this from a patient diagnosed with the placenta accreta spectrum (PAS)…

Many have never heard of PAS, where the placenta grows past the endometrial lining of the uterus and into or beyond the uterine wall. Blood vessels tend to be engorged due to the increased uterine blood supply to support pregnancy. New, abnormal vessels are recruited. This makes surgical management tricky at best and the risk for massive hemorrhage a reality at worst.

The good news is that antenatal identification of PAS has been proven in multiple observational studies to lead to improved outcomes. Why? Antenatal detection allows patients to be referred to centers with experienced, multi-disciplinary PAS teams.

In the U.S., a majority of patients with PAS undergo a cesarean hysterectomy, the definitive surgical approach. Other centers may offer alternative approaches, including delayed hysterectomy, partial myometrial resection, or truly conservative management, where the placenta is left in place after delivery until the placenta resorbs, gets expelled, or complications arise. No matter the approach, the risk for major morbidity and mortality is proven to be lower when patients are cared for by experienced, multidisciplinary teams.

PAS encompasses placenta accreta, increta, and percreta, and truly represents a broad spectrum of abnormal placentation.

Why the sudden interest in PAS?

Many experts believe that the incidence of PAS is rising worldwide. Most large population-based studies show that the incidence ranges more consistently between 1 in 1000 to 5 per 10,000 pregnancies. While these rates are lower than traditionally cited (1 in 200 to 500 deliveries, as cited from referral centers), the increased risk for morbidity and mortality drive the need for vigilance when evaluating patients. PAS can be detected with ultrasound with 80–95% sensitivity and specificity in expert centers, but the overall antenatal detection rate runs closer to 40–50% according to population-based studies.

How is PAS detected before delivery?

Ultrasound is the cornerstone, as it is noninvasive, relatively inexpensive, and readily available. Some experts consider referral to MRI if the placenta is not adequately seen. MRI is not a superior, however, but rather it permits visualization of the placenta in a different way. The sensitivities and specificities of ultrasound and MRI are similar. As with imaging modality, diagnostic accuracy depends upon the expertise of the people acquiring and interpreting the images. Referral to experienced imaging centers is recommended for patients with significant risk factors or if PAS is suspected.

What are the risk factors for PAS?

Most commonly, previous cesarean deliveries and placenta previa. Other risk factors include myomectomy, endometrial ablation, smoking, and in vitro fertilization.

How can we improve antenatal ultrasound detection?

Using standardized protocols and checklists to “prime the mind” are important.  One cannot find what one does not seek, therefore, it is important to evaluate the placenta thoroughly.

A few quick tips:

  1. Fill the bladder. The full bladder creates an acoustic window that improves visualization of the lower segment. Irregular placental bulging and hypervascularity can also be seen with better accuracy.
  2. Angle matters. The lower uterine segment curves away from (perpendicular to) the transabdominal probe. This causes shadowing. Position the patient bed head down and angle the probe such that the handle parallels the patient’s thighs and the lowermost segment appears clearly.
  3. Image transvaginally. Using a transvaginal approach identifies deep, cervical invasion and can provide a clear view of the lower uterine segment.
  4. Interrogate the ENTIRE placental surface. Sweep sagitally left to right, transversely both the midline and along each (to look for parametrial involvement).
  5. 3D and color Doppler. These imaging tools can help identify hypervascularity and bladder contour irregularities.

If there were ever a silver lining, the spotlight on PAS as is fueling us all to work to identify best practices and to improve training at all levels.

Karin A. Fox, MD, MEd, FACOG, is an Associate Professor, Associate Fellowship Director, and Clinical Director of the Placenta Accreta Spectrum Care Team in the Division of Maternal-Fetal Medicine, Department of OB-GYN, at Baylor College of Medicine, as well as is Medical Director of Maternal Transport for the Kangaroo Crew at Texas Children’s Hospital Pavilion for Women.

Interested in learning more about placenta accreta spectrum? Check out the following resources: