Ultrasound for Pregnancy
Number: 0199
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses ultrasound for pregnancy.
-
Medical Necessity
Aetna considers the following indications medically necessary unless otherwise stated:
- Ultrasounds are considered not medically necessary if done solely to determine the fetal sex or to provide parents with a view and photograph of the fetus;
- Fetal ultrasound with detailed anatomic examination for any of the following indications:
- To evaluate the fetus for amniotic band syndrome (also known as amniotic constriction band syndrome); or
- To evaluate fetuses with single umbilical artery (SUA); or
- To evaluate fetuses with soft sonographic markers of aneuploidy:
- Absent or hypoplastic nasal bone; or
- Choroid plexus cyst; or
- Echogenic bowel; or
- Echogenic intracardiac focus; or
- Fetal pyelectasis; or
- Increased nuchal translucency (fetal nuchal translucency measurement of 3.0 mm or greater in the first trimester); or
- Shortened long bones (femur or humerus); or
-
When there are known or suspected fetal anatomic abnormalities, including:
- Abnormal serum markers screening for fetal aneuploidy (triple or quad screening) (see CPB 0464 - Serum and Urine Marker Screening for Fetal Aneuploidy); or
- Anatomic abnormalities due to genetic conditions (see attached ICD-10 coding); or
- Pregnancies resulting from in vitro fertilization (IVF); or
- Obesity (pre-pregnancy body mass index [BMI] of 30 kg/m2 or more) complicating pregnancy; or
- Known or suspected exposure to Zika virus; or
- Pregnancy in woman with untreated or inadequately treated syphilis; or
- Previous pregnancy with a fetus that had an omphalocele or other ultrasound detectable congenital anomaly associated with an elevated risk of recurrence in the current pregnancy; or
- To evaluate the fetus of a mother who has a bicornuate uterus or uterus didelphys; or
- To evaluate pregnant member with Arnold Chiari malformation type 1; or
- To evaluate pregnant member with maternal history of Klippel-Trenaunay syndrome; or
- To diagnose / evaluate uterus didelphys; or
- Use of detailed fetal US at 20 weeks based on previous pregnancy with a child with DiGeorge syndrome;
Note: More than 1 detailed fetal anatomic ultrasound (US) in the 1st trimester and more than 1 detailed fetal anatomic US in the 2nd semester are considered not medically necessary.
-
A limited duplex scan is considered medically necessary for the following obstetric indications:
- Vaginal bleeding in the second or third trimester; or
- Placenta accreta spectrum (accreta, increta, percreta), suspected on ultrasound, in second or third trimester; or
- Abruptio placenta, suspected on ultrasound, in the second or third trimester; or
- Ectopic pregnancy, for evaluation of suspected ectopic pregnancy (pain or bleeding) in the first trimester when an adnexal mass is confirmed on ultrasound; or
- Cornual (interstitial) or C-section scar ectopic pregnancy is suspected on ultrasound, for further vascular assessment; or
- Chorioangioma or umbilical cord varix, to assess vascular flow patterns associated with these conditions; or
- Other placental and cord abnormalities, for evaluating vascular flow in these scenarios:
- Placental hemangioma
- Succenturiate placenta or accessory lobe
- Hypo/hyper-coiled umbilical cord
- Marginal Cord Insertion
- Umbilical cord cyst
- Velamentous cord insertion;
-
A limited duplex scan is considered not medically necessary for assessment of threatened miscarriage in members with vaginal bleeding during first trimester.
-
Experimental, Investigational, or Unproven
The following indications are considered experimental, investigational, or unproven because the effectiveness of these approaches has not been established:
- More than 2 detailed ultrasound fetal anatomic examination per pregnancy per practice, as there is inadequate evidence of the clinical utility of more than 2 serial detailed fetal anatomic ultrasound examinations during pregnancy;
- Complete duplex scan during pregnancy;
- Detailed ultrasound fetal anatomic examination for all other indications including the following:
- Evaluation of hypo-coiled / hyper-coiled umbilical cord
- Evaluation of members with 1st trimester exposure to amphetamine and dextroamphetamine (Adderall) or spironolactone (Aldactone)
- Evaluation of members with family history of congenital heart defect
- Evaluation of members with suspected placenta previa
- Evaluation of members who are pregnant with a low fetal fraction
- Evaluation of members who are/were treated with belimumab (Benlysta)
- Evaluation of members who handled 6-mercaptopurine and methotrexate
- Evaluation of pregnancy in which father of baby has a history of open spinal bifida
- Evaluation of pregnant members with a history of congenital atrophic kidney
- McCune-Albright syndrome
- Members with HIV
- Placental cord insertion (e.g., marginal cord insertion and velamentous insertion of umbilical cord)
- Pregnant women with low pregnancy-associated plasma protein A
- Pregnant women with myasthenia gravis
- Pregnant women who are on bupropion (Wellbutrin) or levetiracetam (keppra)
- Pregnant women who smoke or abuse cannabis
- Routine evaluation of pregnant women who are on azathioprine (Imuran)
- Septate or arcuate uterus;
There is inadequate evidence of the clinical utility of detailed ultrasound fetal anatomic examination for indications other than evaluation of suspected fetal anatomic abnormalities.
Detailed ultrasound fetal anatomic examination is not considered medically necessary for routine screening of normal pregnancy, or in the setting of maternal idiopathic pulmonary hemosiderosis;
-
Three-dimensional (3D) and four-dimensional (4D) fetal ultrasounds because of a lack of evidence that 3D and 4D ultrasounds alter management over standard two-dimensional (2D) ultrasounds such that clinical outcomes are improved.
-
Policy Limitations and Exclusions
Note: Pelvic ultrasound is considered to be clinically integral to the transvaginal examination and does not warrant separate reimbursement. A transvaginal ultrasound (TV-US) provides superior detail in images of pelvic structures. When TV-US is performed on a patient whose pelvic structures are within the bony pelvis, pelvic echography using an abdominal approach is duplicative of the TV-US.
-
Related Policies
- CPB 0088 - Antepartum Fetal Surveillance
- CPB 0106 - Fetal Echocardiography and Magnetocardiography
- CPB 0282 - Noninvasive Down Syndrome Screening - for Aetna's policy on first trimester ultrasonographic assessment of fetal nuchal skinfold thickness
- CPB 0464 - Maternal Biomarker Screening for Fetal Conditions
Background
This policy is based in part on The American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on Ultrasonography in Pregnancy and guidelines from the Society for Maternal-Fetal Medicine (SMFM).
Ultrasonography in pregnancy should be performed only when there is a valid medical indication. ACOG (2009) stated, "The use of either two-dimensional or three-dimensional ultrasonography only to view the fetus, obtain a picture of the fetus, or determine the fetal sex without a medical indication is inappropriate and contrary to responsible medical practice."
Indications for a first-trimester ultrasound (performed before 13 weeks and 6 days of gestation) include:
- As adjunct to chorionic villus sampling, embryo transfer, or localization and removal of an intra-uterine device
- To assess for certain fetal anomalies, such as anencephaly, in patients at high risk
- To confirm cardiac activity
- To confirm the presence of an intra-uterine pregnancy
- To diagnosis or evaluate multiple gestations
- To estimate gestational age
- To evaluate a suspected ectopic pregnancy
- To evaluate maternal pelvic or adnexal masses or uterine abnormalities
- To evaluate pelvic pain
- To evaluate suspected hydatidiform mole
- To evaluate vaginal bleeding
- To screen for fetal aneuploidy.
ACOG recommended that in the absence of specific indications, the optimal time for an obstetric ultrasound examination is between 18 to 20 weeks of gestation because anatomically complex organs, such as the fetal heart and brain, can be imaged with sufficient clarity to allow detection of many major malformations. This recommendation is based primarily on consensus and expert opinion (Level C). ACOG stated that it may be possible to document normal structures before 18 weeks of gestation but some structures can be difficult to visualize at that time because of fetal size, position, and movement; maternal abdominal scars; and increased maternal abdominal wall thickness. A second or third trimester ultrasound examination, however, may pose technical limitations for an anatomic evaluation due to suboptimal imaging, and when this occurs, ACOG recommended documentation of the technical limitation and that a follow-up examination may be helpful.
ACOG uses the terms "standard" (also called basic), "limited," and "specialized" (also called detailed) to describe various types of ultrasound examinations performed during the second or third trimesters.
Standard Examination
A standard ultrasound includes an evaluation of fetal presentation, amniotic fluid volume, cardiac activity, placental position, fetal biometry, and fetal number, plus an anatomic survey. A standard examination of fetal anatomy includes the following essential elements:
- Abdomen (stomach, kidneys, bladder, umbilical cord insertion site into the fetal abdomen, umbilical cord vessel number)
- Chest (heart)
- Extremities (presence or absence of legs and arms)
- Head, face and neck (cerebellum, choroid plexus, cisterna magna, lateral cerebral ventricles, midline falx, cavum septi pellucidi, upper lip)
- Sex (medically indicated in low-risk pregnancies only for the evaluation of multiple gestations).
- Spine (cervical, thoracic, lumbar, and sacral spine).
Limited Examination
A limited examination does not replace a standard examination and is performed when a specific question requires investigation (e.g., to confirm fetal heart activity in a patient experiencing vaginal bleeding or to establish fetal presentation during labor). A limited examination may be performed during the first trimester to evaluate interval growth, estimate amniotic fluid volume, evaluate the cervix, and assess the presence of cardiac activity.
Specialized Examination
A detailed or targeted anatomic examination is performed when an anomaly is suspected on the basis of history, laboratory abnormalities, or the results of either the limited or standard examination. Other specialized examinations might include fetal Doppler ultrasonography, biophysical profile, amniotic fluid assessment, fetal echocardiography, or additional biometric measurements. Specialized examinations are performed by an operator with experience and expertise in such ultrasonography who determines that components of the examination on a case-by-case basis.
Indications for a second and third trimester ultrasound include the following:
- Adjunct to amniocentesis or other procedure
- Adjunct to cervical cerclage placement
- Adjunct to external cephalic version
- Determination of fetal presentation
- Estimation of gestational age
- Evaluation for abnormal biochemical markers
- Evaluation for fetal well-being
- Evaluation for premature rupture of membranes of premature labor
- Evaluation in those with a history of previous congenital anomaly
- Evaluation of abdominal and pelvic pain
- Evaluation of cervical insufficiency
- Evaluation of fetal condition in late registrants for prenatal care
- Evaluation of fetal growth
- Evaluation of pelvic mass
- Evaluation of suspected amniotic fluid abnormalities
- Evaluation of suspected ectopic pregnancy
- Evaluation of suspected fetal death
- Evaluation of suspected multiple gestation
- Evaluation of suspected placental abruption
- Evaluation of suspected uterine abnormality (e.g., bicornuate uterus)
- Evaluation of vaginal bleeding
- Examination of suspected hydatidiform mole
- Follow-up evaluation of a fetal anomaly
- Follow-up evaluation of placental location for suspected placenta previa
- Significant discrepancy between uterine size and clinical dates
- To assess for findings that may increase the risk of aneuploidy
- To screen for fetal anomalies.
The Society for Maternal-Fetal Medicine (SMFM) has stated that a fetal ultrasound with detailed anatomic examination (CPT 76811) is not necessary as a routine scan for all pregnancies (SMFM, 2004). Rather, this scan is necessary for a known or suspected fetal anatomic or genetic abnormality (i.e., previous anomalous fetus, abnormal scan this pregnancy, etc.), or increased risk for fetal abnormality (e.g. AMA, diabetic, fetus at risk due to teratogen or genetics, abnormal prenatal screen). Thus, the SMFM has stated that the performance of this scan is expected to be rare outside of referral practices with special expertise in the identification of, and counseling about, fetal abnormalities (SMFM, 2004; SMFM, 2012).
The Society for Maternal Fetal Medicine (SMFM, 2025) explained that “in light of evolving medical practices and the consensus among major imaging and women's health organizations, there is a compelling need to adapt this code [for detailed fetal anatomic ultrasound] for dual utilization during pregnancy”. The SMFM statement explained that detailed obstetrical ultrasound is typically used at the end of the 1st trimester and again in the 2nd/3rd trimester per pregnancy.
A focused ultrasound assessment is sufficient for follow-up to provide a re-examination of a specific organ or system known or suspected to be abnormal, or when doing a focused assessment of fetal size by measuring the bi-parietal diameter, abdominal circumference, femur length, or other appropriate measurements (SMFM, 2004).
An ultrasound without detailed anatomic examination is appropriate for a fetal maternal evaluation of the number of fetuses, amniotic/chorionic sacs, survey of intra-cranial, spinal and abdominal anatomy, evaluation of a 4-chamber heart view, assessment of the umbilical cord insertion site, assessment of amniotic fluid volume, and evaluation of maternal adenexa when visible and appropriate (SMFM, 2004).
Amniotic band sequence refers to a highly variable spectrum of congenital anomalies that occur in association with amniotic bands. Amniotic banding affects approximately 1 in 1,200 live births. It is also believed to be the cause of 178 in 10,000 miscarriages. Up to 50% of cases have other congenital anomalies including cleft lip, cleft palate, and clubfoot deformity. Hand and finger anomalies occur in up to 80%. The diagnosis is based upon the presence of characteristic structural findings on prenatal ultrasound or postnatal physical examination. The diagnosis should be suspected when limb amputations or atypical body wall or craniofacial defects are present, or when bands of amnion are seen crossing the gestational sac and adherent to the fetus.
In a practice bulletin on screening for fetal chromosomal anomalies, ACOG (2007) has stated that patients who have a fetal nuchal translucency measurement of 3.5 mm or greater in the first trimester, despite a negative result on an aneuploidy screen, normal fetal chromosomes, or both, should be offered a targeted ultrasound examination, fetal echocardiogram, or both, because such fetuses are at a significant risk for non-chromosomal anomalies, including congenital heart defects, abdominal wall defects, diaphragmatic hernias, and genetic syndromes.
An UpToDate review on “First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18” (Messerlian et al., 2021) states that “The best interpretation of nuchal translucency [NT] is by screening programs that combine its measurement with maternal age and first trimester serum markers to provide a patient specific risk of Down syndrome. One exception to this recommendation is for fetuses with a cystic hygroma or significantly enlarged NT. These pregnancies are at particularly high risk of aneuploidy. Many experts proceed directly to karyotype (some choose microarray) assessment in these cases, rather than checking maternal serum analyte levels. The optimum threshold for proceeding to chromosomal analysis without maternal serum screening is unclear. NT thresholds in the range of 3.0 to 4.0 mm have been suggested, given the relatively high risk of Down syndrome at this level”.
The ACOG practice bulletin on the use of psychiatric medications during pregnancy and lactation (2008) stated that atypical anti-depressants are non-tricyclic anti-depressants and non-selective serotonin reuptake inhibitors antidepressants that work by distinct pharmacodynamic mechanisms. The atypical anti-depressants include bupropion, duloxetine, mirtazapine, nefazodone, and venlafaxine. The limited data of fetal exposure to these anti-depressants do not suggest an increased risk of fetal anomalies or adverse pregnancy events. In the one published study of bupropion exposure in 136 patients, a significantly increased risk of spontaneous abortion, but not an increased risk of major malformations, was identified. In contrast, the bupropion registry maintained at GlaxoSmithKline has not identified any increased risk of spontaneous abortion, although these data have not undergone peer review.
In a Cochrane review, Stampalija and colleagues (2010) evaluated the effects on pregnancy outcome, and obstetric practice, of routine utero-placental Doppler ultrasound in first and second trimester of pregnancy in pregnant women at high- and low-risk of hypertensive complications. These investigators searched the Cochrane Pregnancy and Childbirth Group's Trials Register (June 2010) and the reference lists of identified studies. Randomized and quasi-randomized controlled trials of Doppler ultrasound for the investigation of utero-placental vessel waveforms in first and second trimesters compared with no Doppler ultrasound were included in this review. These researchers excluded studies where uterine vessels have been assessed together with fetal and umbilical vessels. Two authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. They found 2 studies involving 4,993 participants. The methodological quality of the trials was good. Both studies included women at low-risk for hypertensive disorders, with Doppler ultrasound of the uterine arteries performed in the second trimester of pregnancy. In both studies, pathological finding of uterine arteries was followed by low-dose aspirin administration. They identified no difference in short-term maternal and fetal clinical outcomes; identified no randomized studies assessing the utero-placental vessels in the first trimester or in women at high-risk for hypertensive disorders. The authors concluded that present evidence failed to show any benefit to either the baby or the mother when utero-placental Doppler ultrasound was used in the second trimester of pregnancy in women at low-risk for hypertensive disorders. However, this evidence can not be considered conclusive with only 2 studies included. There were no randomized studies in the first trimester, or in women at high-risk. They stated that more research is needed to examine if the use of utero-placental Doppler ultrasound may improve pregnancy outcome.
The American Institute for Ultrasound Medicine, the Society for Maternal Fetal Medicine, and other societies (Wax et al., 2015) recommended a threshold BMI of greater than or equal to 30 kg/m2 for performing a detailed fetal anatomic ultrasound for pregnancy complicated by obesity. A previous AIUM and SMFM report (Wax, et al., 2014) referred to and increased body mass index (BMI, ≥35 kg/m2) as the threshold for the detailed fetal anatomic ultrasound. However, the AIUM noted that "both of the cited publications [citing Rasmussen et al., 2008; Stothard et al., 2009] quote articles that use varied definitions of obesity based on pre-pregnancy or early pregnancy BMI but are closer to the more standard definition of BMI ≥30 kg/m2, which should therefore be the definition of obesity for the purposes of indicating a 76811 examination."
Fetal ultrasound with detailed anatomic examination is recommended to further evaluate single umbilical artery found on initial imaging. Typically the umbilical cord contains two arteries and one vein; however, a variation of umbilical cord anatomy may occur resulting in a single umbilical artery (SUA). SUA may be an isolated finding, or associated with aneuploidy or other congenital anomalies. Prevalence depends on the characteristics of the population studied. SUA is more common in pregnancies at "the extremes of maternal age and in Eastern Europeans", as well as, in twin pregnancies (3.9 to 8.8 percent). SUA is a finding that is found on an obstetrical ultrasound examination. The American Institute of Ultrasound in Medicine recommends imaging the umbilical cord as part of a standard prenatal ultrasound examination and evaluating the number of vessels in the cord, when possible, in the second and third trimesters. SUA can be detected in the first trimester; however, the sensitivity and specificity are higher in the second trimester. SUA occurs in approximately 0.5 percent of unselected pregnancies undergoing second-trimester ultrasound examination (Gimovsky et al., 2018).
The Society for Maternal-Fetal Medicine (SMFM, 2013) state that SUA can usually be detected on cross-section of the umbilical cord using 2-D imaging. SMFM recommends further SUA evaluation to include a detailed anatomic survey by an experienced provider, and include assessment of risk factors for aneuploidy, including maternal age, results of other screening or diagnostic tests, and family history.
Three-Dimensional and Four-Dimensional Ultrasound in Obstetrics
Three-dimensional (3D) ultrasound can furnish a 3D image of the fetus. To create a 3D image, a transducer takes a series of thin slices of the subject, and a computer translates these images and presents them in three dimensions.
Proponents of 3D ultrasound scanning argue that volumetric measurements from 3D ultrasound scans are more accurate and that both clinicians and parents can better appreciate certain abnormalities with a 3D scan than with a standard two-dimensional (2D) scan. Additionally, there is the possibility of increasing psychological bonding between the parents and the baby (Ji et al., 2005).
In the diagnosis of congenital anomalies, evidence suggests that smaller defects such as spina bifida, cleft lip and palate, and polydactyly may be more clearly demonstrated with 3D ultrasound (Gonçalves et al., 2005; Kurjak et al., 2007). Other subtle features, such as low-set ears, facial dysmorphia, or clubbing of feet, may be better assessed, potentially leading to more effective diagnoses of chromosomal abnormalities.
Furthermore, the use of 3D technology can reduce scanning time while maintaining adequate visualization of the fetus in obstetrical ultrasound (Benacerraf et al., 2005; Benacerraf et al., 2006).
Jones et al. (2010) examined the intra- and inter-observer reproducibility of 3D power Doppler (3DPD) data acquisition from women at 12 weeks gestation, which were subsequently measured by a single observer. Women with an uncomplicated, viable singleton pregnancy were scanned between 12 + 0 and 13 + 6 weeks gestation with a Voluson 730 Expert. 3DPD data were acquired of the whole placenta by two observers: the first observer captured two datasets, and the second a single dataset. Each dataset was analyzed using VOCAL in the A plane with 9-degree rotation steps. A total of 18 low-risk women were recruited, with a total of 54 datasets analyzed. The intra-class correlation coefficient (ICC) was highest for the vascular indices vascularization index (VI) and vascularization-flow index (VFI), both greater than 0.75. The intra-class correlation coefficient for flow index (FI) showed moderate correlation at 0.47 to 0.65. Bland-Altman plots indicated that the most precise vascular index was the FI (-15% to 10% for inter-observer agreement), with no bias between datasets. Prospective studies are now required to determine if this analysis tool and method are sensitive enough to recognize patients with early-onset placental dysfunction.
More recently, four-dimensional (4D) or dynamic 3D scanners have come on the market, allowing observation of fetal movements. These have also been referred to as "reassurance scans" or "entertainment scans." Proponents argue that 4D scans may have an important catalytic effect for mothers to bond with their babies before birth. However, the impact of 4D scans on the diagnosis and management of fetal abnormalities is unknown.
Three-dimensional ultrasound appears to have been useful in research on fetal embryology. However, there is no evidence that the results of 3D ultrasound alter clinical management compared to standard 2D ultrasound in a way that improves clinical outcomes. Whether 3D ultrasound will provide unique, clinically relevant information remains to be seen.
Current guidelines on ultrasonography in pregnancy from ACOG (2009) state: "The technical advantages of 3-dimensional ultrasonography include its ability to acquire and manipulate an infinite number of planes and to display ultrasound planes traditionally inaccessible by 2-dimensional ultrasonography. Despite these technical advantages, proof of a clinical advantage of 3-dimensional ultrasonography in prenatal diagnosis in general is still lacking. Potential areas of promise include fetal facial anomalies, neural tube defects, and skeletal malformations where 3-dimensional ultrasonography may be helpful in diagnosis as an adjunct to, but not a replacement for, 2-dimensional ultrasonography. Until clinical evidence shows a clear advantage to conventional 2-dimensional ultrasonography, 3-dimensional ultrasonography is not considered a required modality at this time."
Yagel et al. (2009) described the state of the science of 3D/4D ultrasound (3D/4D US) applications in fetal medicine. They noted that 3D/4D US applications are many and varied. Their use in fetal medicine varies with the nature of the tissue to be imaged and the challenges each organ system presents, versus the advantages of each ultrasound application. The investigators stated that 3D/4D US has been extensively applied to the study of the fetus. Fetal applications include all types of anatomical assessment, morphometry, and volumetry, as well as functional assessment. The authors concluded that 3D/4D US provides many advantages in fetal imaging; however, its contribution to improving the accuracy of fetal scanning over rates achieved with 2D US remains to be established.
In a prospective study, Chen et al. (2009) examined the feasibility and reproducibility of measurements of nasal bone length using 3D US in the first trimester. A total of 118 consecutive pregnant women attending for Down syndrome screening at 11 to 13(+6) weeks were recruited. They had successful fetal nasal bone measurement by 2D US by four operators. Three-dimensional volumes were recorded in the mid-sagittal plane of the fetal profile by the fifth operator and examined using multi-planar techniques. Another independent investigator randomly compared his measurements with one of the four operators. In the subsequent 3D examination, the nasal bone length could be examined in 94 cases (79.7%). The mean difference between the 2D and 3D measurements was 0.19 mm [95% confidence interval (CI): 0.08 to 0.31] (p < 0.05). Limits of agreement were -0.73 to 1.11. The mean differences between these two observers were 0.66 mm (95% CI: -0.47 to 0.86) (p < 0.05). The authors concluded that there was a significant inter-method difference between the results obtained by 2D and 3D, as well as substantial inter-observer variation in 3D measurement of fetal nasal bone length in the first trimester. They stated that independent 3D measurement of nasal bone offers no additional advantages over 2D US.
Kurjak and colleagues (2010) stated that an evolving challenge for obstetricians is to better define normal and abnormal fetal neurological function in utero to better predict antenatally which fetuses are at risk for adverse neurological outcomes. In a multi-center study, these investigators examined the use of 4D US in the assessment of fetal neurobehavior in high-risk pregnancies. Prenatal neurological assessment was carried out in high-risk fetuses using 4D US, applying the recently developed Kurjak ante-natal neurodevelopmental test (KANET). Post-natal neurological assessment was performed using Amiel Tison's neurological assessment at term (ATNAT) for all live-borns and general movement (GM) assessment for those with borderline and abnormal ATNAT. Inclusion criteria were met by 288 pregnant women in four centers, of whom 266 gave birth to a live-born baby. It was revealed that 234 fetuses were neurologically normal, 7 abnormal, and 25 borderline. Out of 7 abnormal fetuses, ATNAT was borderline in 5 and abnormal in 2, whereas GM assessment was abnormal in 5 and definitely abnormal in 2. Out of 25 KANET borderline fetuses, ATNAT was normal in 7, borderline in 17, and abnormal in 1, whereas the GM assessment was as follows: normal optimal in 4, normal suboptimal in 20, and abnormal in 1. In summary, out of 32 borderline and abnormal fetuses, ATNAT was normal in 7, borderline in 22, and abnormal in 3; GM assessment was normal optimal in 4, normal suboptimal in 20, abnormal in 6, and definitely abnormal in 2. The authors concluded that 4D US requires further studies before being recommended for wider clinical practice.
Hata et al. (2011) presented two cases of amniotic band syndrome diagnosed using 2D ultrasound with 3D/4D ultrasound in early pregnancy. In case 1, at 13 weeks' gestation, multiple amniotic bands, acrania, the absence of fingers, and amputation of the toes bilaterally were clearly shown using trans-vaginal 3D/4D ultrasound. In case 2, at 15 weeks' gestation, several amniotic bands, acrania, and a cleft lip were depicted with trans-abdominal 3D/4D ultrasound. The spatial relationship between the amniotic bands and the fetus was clearly visualized and easily discernible by 3D/4D ultrasound. The parents and families could readily understand the fetal conditions and undergo counseling; they then chose the option of termination of pregnancy. The authors concluded that 3D/4D ultrasound has the potential to supplement conventional 2D ultrasound in evaluating amniotic band syndrome.
In a pilot study, Antsaklis et al. (2011) evaluated the use of 3D ultrasonography as an alternative for examining fetal anatomy and nuchal translucency (NT) in the first trimester of pregnancy. A total of 199 low-risk pregnant women undergoing first-trimester ultrasound scans for fetal anomalies were included in this study. The NT and fetal anatomy were evaluated by 3D ultrasonography after the standard 2D examination. The gold standard in this study was the 2D ultrasonography. In some of the evaluated parameters, the 3D method approached the conventional 2D results. These parameters include crown-rump length (CRL), skull-brain anatomy (93.5%), spine (85.4%), upper limbs (88.4%), lower limbs (87.9%), and examination of the fetal abdomen (98.5%). Some of the anatomic parameters under evaluation revealed a statistically significant difference in favor of the 2D examination. During the 3D examination, the nasal bone was identified in 62.1% of the cases, the stomach in 85.9%, and the urinary bladder in 57.3% of the cases. The NT was assessed accurately in 50% of the cases compared to the 2D examination. The authors concluded that the 3D ultrasound is insufficient for detailed fetal anatomy examination during the first trimester of pregnancy.
According to the Product Insert of Keppra (Pregnancy Category C), there are no adequate and well-controlled studies in pregnant women. In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. Keppra should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. As with other anti-epileptic drugs, physiological changes during pregnancy may affect levetiracetam concentration. There have been reports of decreased levetiracetam concentration during pregnancy. Discontinuation of anti-epileptic treatments may result in disease worsening, which can be harmful to the mother and the fetus.
In a Cochrane review, Grivell et al. (2012) noted that policies and protocols for fetal surveillance in pregnancies where impaired fetal growth is suspected vary widely, with numerous combinations of different surveillance methods. These researchers evaluated the effects of ante-natal fetal surveillance regimens on important perinatal and maternal outcomes. They searched the Cochrane Pregnancy and Childbirth Group's Trials Register (February 29, 2012). Randomized and quasi-randomized trials comparing the effects of described ante-natal fetal surveillance regimens were selected for analysis. Review authors independently assessed trial eligibility and quality and extracted data. They included one trial of 167 women and their babies. This trial was a pilot study recruiting alongside another study; therefore, a separate sample size was not calculated. The trial compared a twice-weekly surveillance regimen (biophysical profile, non-stress tests, umbilical artery and middle cerebral artery Doppler, and uterine artery Doppler) with the same regimen applied fortnightly (both groups had growth assessed fortnightly). There were insufficient data to assess this review's primary infant outcome of composite perinatal mortality and serious morbidity (although there were no perinatal deaths), and no difference was seen in the primary maternal outcome of emergency caesarean section for fetal distress (risk ratio (RR) 0.96; 95% CI: 0.35 to 2.63). In keeping with the more frequent monitoring, the mean gestational age at birth was 4 days less for the twice-weekly surveillance group compared with the fortnightly surveillance group (mean difference (MD) -4.00; 95% CI: -7.79 to -0.21). Women in the twice-weekly surveillance group were 25% more likely to have induction of labor than those in the fortnightly surveillance group (RR 1.25; 95% CI: 1.04 to 1.50). The authors concluded that there is limited evidence from randomized controlled trials to inform best practice for fetal surveillance regimens when caring for women with pregnancies affected by impaired fetal growth. They stated that more studies are needed to evaluate the effects of currently used fetal surveillance regimens in impaired fetal growth.
A choroid plexus cyst is a small fluid-filled structure within the choroid of the lateral ventricles of the fetal brain. Choroid plexus cysts are identified in approximately 1% to 2% of fetuses in the second trimester, and they occur equally in male and female fetuses. According to the Society for Maternal-Fetal Medicine (SMFM, 2013), when a choroid plexus cyst is identified, the presence of structural malformations and other sonographic markers of aneuploidy should be assessed with a detailed fetal anatomic survey performed by an experienced provider. A detailed examination of the fetal heart (4-chamber view and outflow tracts view) and hands (for “clenching” or other abnormal positioning) should be included, as well as fetal biometry for assessment of intrauterine growth restriction. If no other sonographic abnormalities are present, the choroid plexus cyst is considered isolated.
Gindes et al. (2013) evaluated the ability of 3D ultrasound to demonstrate the palate of fetuses at high risk for cleft palate. A total of 57 fetuses at high risk for cleft palate were referred to a specialist for ultrasonography at 12 to 40 weeks' gestation. A detailed assessment of the palate was made using both 2D and 3D ultrasounds on the axial plane. Antenatal diagnoses were compared with post-natal findings. Cleft palate was suspected in 13 (22.8%); a normal palate was demonstrated in 38 (67%), and in 6 (10.2%), the palate view could not be obtained. The mean gestational age at the first visit was 27 weeks 6 days (range of 12 to 40 weeks 3 days). Examination after delivery revealed that 1 of the 38 fetuses with presumed normal palate had a cleft hard palate, and 1 had a cleft soft palate (false negative = 5%). Among the 13 fetuses with suspected cleft palate, 3 had an intact palate (false positive = 23%). Sensitivity, specificity, positive predictive value, and negative predictive value of detection of palatal clefts were 71.4%, 91.9%, 62.5%, and 94.4%, respectively. The authors concluded that using 3D ultrasounds, they diagnosed a cleft palate in 83% of high-risk cases, with a 5% false negative. They stated that 3D technology might produce some technical artifacts resulting in a 23% false-positive rate.
Kanenishi et al. (2013) evaluated the frequency of fetal facial expressions at 25 to 27 weeks of gestation using 4D ultrasound. A total of 24 normal fetuses were examined using 4D ultrasound. The face of each fetus was recorded continuously for 15 minutes. The frequencies of tongue expulsion, yawning, sucking, mouthing, blinking, scowling, and smiling were assessed and compared with those observed at 28 to 34 weeks of gestation in a previous study. Mouthing was the most common facial expression at 25 to 27 weeks of gestation; the frequency of mouthing was significantly higher than that of the other six facial expressions (p < 0.05). Yawning was significantly more frequent than the other facial expressions, apart from mouthing (p < 0.05). The frequencies of yawning, smiling, tongue expulsion, sucking, and blinking differed significantly between 25 to 27 and 28 to 34 weeks (p < 0.05). The authors concluded that the results indicated that facial expressions can be used as an indicator of normal fetal neurologic development from the second to the third trimester. They stated that 4D ultrasound may be a valuable tool for assessing fetal neurobehavioral development during gestation. These preliminary findings need to be validated by well-designed studies.
Votino et al. (2013) evaluated prospectively the use of 4D spatio-temporal image correlation (STIC) in the evaluation of the fetal heart at 11 to 14 weeks' gestation. The study involved off-line analysis of 4D-STIC volumes of the fetal heart acquired at 11 to 14 weeks' gestation in a population at high risk for congenital heart disease (CHD). Regression analysis was used to investigate the effect of gestational age, maternal body mass index, quality of the 4D-STIC volume, use of a trans-vaginal versus trans-abdominal probe, and use of color Doppler ultrasonography on the ability to visualize different heart structures separately. The accuracy in diagnosing CHD based on early fetal echocardiography (EFE) using 4D-STIC versus conventional 2D ultrasound was also evaluated. A total of 139 fetuses with a total of 243 STIC volumes were included in this study. Regression analysis showed that the ability to visualize different heart structures was correlated with the quality of the acquired 4D-STIC volumes. Independently, the use of a trans-vaginal approach improved visualization of the 4-chamber view, and the use of Doppler improved visualization of the outflow tracts, aortic arch, and inter-ventricular septum. Follow-up was available in 121 of the 139 fetuses, of which 27 had a confirmed CHD. A diagnosis based on EFE using 4D-STIC was possible in 130 (93.5%) of the 139 fetuses. Accuracy in diagnosing CHD using 4D-STIC was 88.7%, and the results of 45% of the cases were fully concordant with those of 2D ultrasound or the final follow-up diagnosis. Early fetal echocardiography using 2D ultrasound was possible in all fetuses, and accuracy in diagnosing CHD was 94.2%; 5 of the 7 false-positive or false-negative cases were minor CHD. The authors concluded that in fetuses at 11 to 14 weeks' gestation, the heart can be evaluated offline using 4D-STIC in a large number of cases, and this evaluation is more successful the higher the quality of the acquired volume. Moreover, they stated that 2D ultrasound remains superior to 4D-STIC at 11 to 14 weeks unless volumes of good to high quality can be obtained.
Ahmed (2014) stated that CHD is the most common congenital anomaly. It is much more common than chromosomal malformations and spinal defects, with an estimated incidence of about 4 to 13 per 1,000 live births. Congenital heart disease is a significant cause of fetal mortality and morbidity. Antenatal diagnosis of CHD is extremely difficult and requires extensive training and expertise. The detection rate of CHD is very variable, ranging from 35% to 86% in most studies. In light of the above, the introduction of the new 3D/4D-based STIC is highly welcomed to improve antenatal detection of CHD. Spatio-temporal image correlation is an automated device incorporated into the ultrasound probe and has the capacity to perform a slow sweep to acquire a single 3D volume. This acquired volume is composed of a great number of 2D frames. This volume can be analyzed and re-analyzed as required to demonstrate all the required cardiac views. It also provides the examiner with the ability to review all images in a looped cine sequence. The author concluded that this technology has the ability to improve the examination of the fetal heart in the acquired volume and decrease examination time; it is a promising tool for the future.
Tonni et al. (2014) described the application of a novel 3D ultrasound reconstructing technique (OMNIVIEW) that may facilitate the evaluation of cerebral midline structures at the second trimester anatomy scan. Fetal cerebral midline structures from 300 consecutive normal low-risk pregnant women were studied prospectively by 2D and 3D ultrasound between 19 to 23 weeks of gestation. All the newborn infants underwent pediatric follow-up and were considered normal up to 2 years of life. In addition, five confirmed pathologic cases were evaluated, and the abnormal features using this technique were described in this clinical series. Off-line volume data sets displaying the corpus callosum and the cerebellar vermis anatomy were accurately reconstructed in 98.5% and 96% of cases from sagittal and axial planes, respectively. For pathological cases, an agreement rate of 0.96 and 0.91 for mid-sagittal and axial planes, respectively, was observed. The authors concluded that this study demonstrated the feasibility of including 3D ultrasound as an adjunct technique for the evaluation of cerebral midline structures in the second trimester fetus. Moreover, they stated that future prospective studies are needed to evaluate if the application of this novel 3D reconstructing technique as a step forward following 2D second trimester screening scans will improve the prenatal detection of cerebral midline anomalies in the low-risk pregnant population.
Sharp et al. (2014) noted that fetal assessment following preterm premature rupture of membranes (PPROM) may result in earlier delivery due to earlier detection of fetal compromise. However, early delivery may not always be in the fetal or maternal interest, and the effectiveness of different fetal assessment methods in improving neonatal and maternal outcomes is uncertain. In a Cochrane review, these researchers examined the effectiveness of fetal assessment methods for improving neonatal and maternal outcomes in PPROM. Examples of fetal assessment methods that would be eligible for inclusion in this review include fetal cardiotocography, fetal movement counting, and Doppler ultrasound. They searched the Cochrane Pregnancy and Childbirth Group's Trials Register (June 30, 2014) and reference lists of retrieved studies. Randomized controlled trials (RCTs) comparing any fetal assessment methods or comparing one fetal assessment method to no assessment were selected for analysis. Two review authors independently assessed trials for inclusion in the review. The same two review authors independently assessed trial quality and extracted data. Data were checked for accuracy. These researchers included three studies involving 275 women (data reported for 271) with PPROM at up to 34 weeks' gestation. All three studies were conducted in the United States. Each study investigated different methods of fetal assessment. One study compared weekly endovaginal ultrasound scans with no assessment (n = 93), one compared amniocentesis with no assessment (n = 47), and one compared daily non-stress testing with daily modified biophysical profiling (n = 135). These investigators were unable to perform a meta-analysis but were able to report data from individual studies. There was no convincing evidence of increased risk of neonatal death in the group receiving endovaginal ultrasound scans compared with the group receiving no assessment (risk ratio (RR) 7.30, 95% CI: 0.39 to 137.54; 1 study, 92 women), or in the group receiving amniocentesis compared with the group receiving no amniocentesis (RR 1.00, 95% CI: 0.07 to 15.00; 1 study, 44 women). For both these interventions, these researchers inferred that there were no fetal deaths in the intervention or control groups. The study comparing daily non-stress testing with daily modified biophysical profiling did not report fetal or neonatal death. Primary outcomes of maternal death and serious maternal morbidity were not reported in any study. Overall, there were few statistically significant differences in outcomes between the comparisons. The overall quality of evidence was poor because participant blinding was not possible for any study. The authors concluded that there is insufficient evidence on the benefits and harms of fetal assessment methods for improving neonatal and maternal outcomes in women with PPROM to draw firm conclusions. The overall quality of evidence that does exist is poor. They stated that further high-quality RCTs are needed to guide clinical practice.
In a Cochrane review, Alfirevic et al. (2015) examined the effects on obstetric practice and pregnancy outcomes of routine fetal and umbilical Doppler ultrasound in unselected and low-risk pregnancies. These investigators searched the Cochrane Pregnancy and Childbirth Group Trials Register (February 28, 2015) and reference lists of retrieved studies. Randomized and quasi-randomized controlled trials of Doppler ultrasound for the investigation of umbilical and fetal vessels waveforms in unselected pregnancies compared with no Doppler ultrasound were selected for analysis. Studies where uterine vessels have been assessed together with fetal and umbilical vessels have been included. Two review authors independently assessed the studies for inclusion, assessed risk of bias, and carried out data extraction. In addition to standard meta-analysis, the two primary outcomes and five of the secondary outcomes were assessed using GRADE software and methodology. These researchers included five trials that recruited 14,624 women, with data analyzed for 14,185 women. All trials had adequate allocation concealment, but none had adequate blinding of participants, staff, or outcome assessors. Overall, apart from the lack of blinding, the risk of bias for the included trials was considered to be low. Overall, routine fetal and umbilical Doppler ultrasound examination in low-risk or unselected populations did not result in increased antenatal, obstetric, and neonatal interventions. There were no group differences noted for the review's primary outcomes of perinatal death and neonatal morbidity. Results for perinatal death were as follows: (average RR 0.80, 95% CI: 0.35 to 1.83; 4 studies, 11,183 participants). Only one included trial assessed serious neonatal morbidity and found no evidence of group differences (RR 0.99, 95% CI: 0.06 to 15.75; 1 study, 2,016 participants). For the comparison of a single Doppler assessment versus no Doppler, evidence for group differences in perinatal death was detected (RR 0.36, 95% CI: 0.13 to 0.99; 1 study, 3,891 participants). However, these results are based on a single trial, and these researchers would recommend caution when interpreting this finding. There was no evidence of group differences for the outcomes of caesarean section, neonatal intensive care admissions, or preterm birth of less than 37 weeks. When the quality of the evidence for the main comparison of “All Doppler versus no Doppler” was assessed with GRADE software, the outcomes of perinatal death and serious neonatal morbidity data were graded as low quality. Evidence for the outcome of stillbirth was graded according to regimen subgroups—with a moderate quality rating for stillbirth (fetal/umbilical vessels only) and a low-quality rating for stillbirth (fetal/umbilical vessels + uterine artery vessels). Evidence for admission to the neonatal intensive care unit was assessed as moderate quality, and evidence for the outcomes of caesarean section and preterm birth of less than 37 weeks was graded as high quality. There was no available evidence to assess the effect on substantive long-term outcomes such as childhood neurodevelopment and no data to assess maternal outcomes, particularly maternal satisfaction. The authors concluded that existing evidence does not provide conclusive evidence that the use of routine umbilical artery Doppler ultrasound, or a combination of umbilical and uterine artery Doppler ultrasound in low-risk or unselected populations benefits either mother or baby. They stated that future studies should be designed to address small changes in perinatal outcomes and should focus on potentially preventable deaths.
In a Cochrane review, Bricker et al. (2015) evaluated the effects on obstetric practice and pregnancy outcomes of routine late pregnancy ultrasound, defined as greater than 24 weeks' gestation, in women with either unselected or low-risk pregnancies. These investigators searched the Cochrane Pregnancy and Childbirth Group's Trials Register (May 31, 2015) and reference lists of retrieved studies. All acceptably controlled trials of routine ultrasound in late pregnancy (defined as after 24 weeks) were selected for analysis. Three review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. A total of 13 trials recruiting 34,980 women were included in the systematic review. Risk of bias was low for allocation concealment and selective reporting, unclear for random sequence generation and incomplete outcome data, and high for blinding of both outcome assessment and participants and personnel. There was no difference in antenatal, obstetric, and neonatal outcomes or morbidity in screened versus control groups. Routine late pregnancy ultrasound was not associated with improvements in overall perinatal mortality. There is little information on long-term substantive outcomes such as neurodevelopment. There is a lack of data on maternal psychological effects. Overall, the evidence for the primary outcomes of perinatal mortality, preterm birth of less than 37 weeks, induction of labor, and caesarean section were assessed to be of moderate or high quality with GRADE software. There was no association between ultrasound in late pregnancy and perinatal mortality (RR 1.01, 95% CI: 0.67 to 1.54; participants = 30,675; studies = 8; I² = 29%), preterm birth of less than 37 weeks (RR 0.96, 95% CI: 0.85 to 1.08; participants = 17,151; studies = 2; I² = 0%), induction of labor (RR 0.93, 95% CI: 0.81 to 1.07; participants = 22,663; studies = 6; I² = 78%), or caesarean section (RR 1.03, 95% CI: 0.92 to 1.15; participants = 27,461; studies = 6; I² = 54%). Three additional primary outcomes chosen for the “Summary of findings” table were preterm birth of less than 34 weeks, maternal psychological effects, and neurodevelopment at age 2. Because none of the included studies reported these outcomes, they were not assessed for quality with GRADE software. The authors concluded that based on existing evidence, routine late pregnancy ultrasound in low-risk or unselected populations did not confer benefit on mother or baby. There was no difference in the primary outcomes of perinatal mortality, preterm birth of less than 37 weeks, caesarean section rates, and induction of labor rates if ultrasound in late pregnancy was performed routinely versus not performed routinely. Meanwhile, data were lacking for the other primary outcomes: preterm birth of less than 34 weeks, maternal psychological effects, and neurodevelopment at age 2, reflecting a paucity of research covering these outcomes. The authors stated that these outcomes may warrant future research.
The Zika virus is a mosquito-borne virus that has been associated with congenital defects, primarily of the central nervous system (SMFM, 2016). According to the Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine, clinicians should screen pregnant women for possible Zika exposure, particularly if they live in or have traveled to areas of active Zika transmission. Pregnant women exposed to Zika or who report clinical illness consistent with the virus should be tested for the virus based on national guidelines. Part of that testing involves fetal ultrasound to detect microcephaly or intracranial calcifications, and in certain cases, amniocentesis may be offered (SMFM, 2016).
Intra-Partum Ultrasound for Diagnosis of Mal-Positions and Cephalic Mal-Presentations
Bellussi and colleagues (2017) noted that fetal mal-positions and cephalic mal-presentations are well-recognized causes of failure to progress in labor. They frequently require operative delivery, and are associated with an increased probability of fetal and maternal complications. Traditional obstetrics emphasizes the role of digital examinations, but recent studies demonstrated that this approach is inaccurate and intra-partum US is far more precise. These investigators summarized the available evidence and provided recommendations to identify mal-positions and cephalic mal-presentations with US. These researchers proposed a systematic approach consisting of a combination of trans-abdominal and trans-perineal scans and described the findings that allow an accurate diagnosis of normal and abnormal position, flexion, and synclitism of the fetal head. The management of mal-positions and cephalic mal-presentation is currently a matter of debate, and individualized depending on the general clinical picture and expertise of the provider. The authors concluded that intra-partum US allows a precise diagnosis and thus offers the best opportunity to design prospective studies with the aim of establishing evidence-based treatment.
Ultrasound for Detection of Thrombosis in Pregnancy
Castro and associates (2017) determined the diagnostic accuracy of US to detect deep-vein thrombosis (DVT) in pregnant patients. These investigators searched PubMed, LILACS, Scopus, Google Scholar and System for Information on Grey Literature from inception to April 2016. The reference lists of the included studies were analyzed. Original articles from accuracy studies that analyzed US to diagnose DVT in pregnant women were included. Reference standard was the follow-up time. The QUADAS-2 score was used for quality assessment. Titles and summaries from 2,129 articles were identified; 4 studies that evaluated DVT in pregnant women were included; a total of 486 participants were enrolled. High risk of bias was seen in 3 out of 4 studies included regarding flow and timing domain of QUADAS-2. Negative predictive value was 99.39%. The authors concluded that accuracy of US to diagnose DVT in pregnant women was not determined due to the absence of data yielding positive results. They stated that further studies of low risk of bias are needed to determine the diagnostic accuracy of US in this clinical scenario.
Ultrasound for Detection of Bicornuate Uterus
A bicornuate uterus has a fundus that is indented 1 cm or more and the vagina and cervix are generally normal. It results from partial rather than complete fusion of the Müllerian ducts. Depending on the extent of fusion, separation of the uterine horns will be complete, partial, or minimal. The diagnosis is based on ultrasound findings of two usually moderately separated (i.e., divergent) endometrial cavities and an indented fundal contour.
Czeizel et al. (2011) studied the potential association between a uterus that is either uni- or bicornis in pregnant women and the occurrence of structural birth defects (i.e., congenital abnormalities) in their offspring. The study analyzed 22,843 cases of congenital abnormalities recorded in the Hungarian Case-Control Surveillance of Congenital Abnormalities from 1980 to 1996, matched against 38,151 controls without any defects. The prevalence of medically recorded uni/bicornate uterus in the prenatal maternity logbooks of mothers with various congenital abnormalities was compared to that of their matched controls. Among the subjects, 57 (0.25%) had mothers with a uni/bicornate uterus, compared to 67 (0.18%) in the control group. The results indicated a significant association between a uni/bicornate uterus in pregnant women and an increased risk of congenital abnormalities overall (adjusted odds ratio of 1.5; 95% confidence interval, 1.1-2.2), primarily driven by a notably higher risk of clubfoot and postural deformities in their children (adjusted odds ratio of 4.7; 95% confidence interval, 2.4-9.1). The authors concluded that pregnant women with a uni/bicornate uterus face a significantly higher risk of clubfoot and postural deformities in their offspring.
Martinez-Frías et al. (1998) noted that most reports concerning mothers with a bicornuate uterus focus on fertility, reproductive capacity, and pregnancy outcomes, with few addressing the risk of congenital anomalies in their offspring. To the authors' knowledge, no epidemiological studies have estimated the risk of congenital defects or analyzed the types of anomalies observed in infants born to mothers with a bicornuate uterus. In their case-control study, the authors assessed 26,945 consecutive malformed infants from the Spanish Collaborative Study of Congenital Malformations to estimate the risk of congenital anomalies in the offspring of women with a bicornuate uterus compared to those born to mothers with a normal uterus. They calculated the relative frequency of individual defects in each group, expressing how much more frequent each congenital defect was in infants of mothers with a bicornuate uterus than in those born to mothers with a normal uterus. The findings revealed that offspring of mothers with a bicornuate uterus had a risk of congenital defects four times higher than those born to women with a normal uterus. This risk was statistically significant for specific defects, including nasal hypoplasia, omphalocele, limb deficiencies, teratomas, and acardia-anencephaly. The authors concluded that infants born to mothers with a bicornuate uterus are at high risk not only for deformations and disruptions but also for certain types of malformations.
Combined Measurement of Placental Biomarkers Plus Ultrasound Assessment of Fetal Growth for the Identification of Placental Dysfunction
Heazell and colleagues (2019) noted that stillbirth affects 2.6 million pregnancies worldwide each year. While the majority of cases occur in low- and middle-income countries, stillbirth remains an important clinical issue for high-income countries (HICs) – with both the United Kingdom and the United States reporting rates above the mean for HICs. In HICs, the most frequently reported association with stillbirth is placental dysfunction. Placental dysfunction may be evident clinically as fetal growth restriction (FGR) and small-for-dates infants. It can be caused by placental abruption or hypertensive disorders of pregnancy and many other disorders and factors. Placental abnormalities are noted in 11% to 65% of stillbirths. Identification of FGA is difficult in-utero. Small-for-gestational age (SGA), as assessed following birth, is the most commonly used surrogate measure for this outcome. The degree of SGA is associated with the likelihood of FGR; 30% of infants with a birth-weight of less than 10th centile are thought to be FGR, while 70% of infants with a birth-weight less than third centile are thought to be FGR. Critically, SGA is the most significant antenatal risk factor for a stillborn infant. Correct identification of SGA infants is associated with a reduction in the perinatal mortality rate. However, currently used tests, such as measurement of symphysis-fundal height, have a low reported sensitivity and specificity for the identification of SGA infants. In a Cochrane review, these researchers compared the diagnostic accuracy of US assessment of fetal growth by estimated fetal weight (EFW) and placental biomarkers alone and in any combination used after 24 weeks of pregnancy in the identification of placental dysfunction as evidenced by either stillbirth, or birth of a SGA infant. Secondary objectives were to examine the effect of clinical and methodological factors on test performance. These investigators developed full search strategies with no language or date restrictions. The following sources were searched: Medline, Medline In Process and Embase via Ovid, Cochrane (Wiley) CENTRAL, Science Citation Index (Web of Science), CINAHL (EBSCO) with search strategies adapted for each database as required; ISRCTN Registry, UK Clinical Trials Gateway, WHO International Clinical Trials Portal and ClinicalTrials.gov for ongoing studies; specialist abstract and conference proceeding resources (British Library's ZETOC and Web of Science Conference Proceedings Citation Index). Search last conducted in October 2016. These investigators included studies of pregnant women of any age with a gestation of at least 24 weeks if relevant outcomes of pregnancy (livebirth/stillbirth; SGA infant) were assessed. Studies were included irrespective of whether pregnant women were deemed to be low or high risk for complications or were of mixed populations (low and high risk). Pregnancies complicated by fetal abnormalities and multi-fetal pregnancies were excluded as they have a higher risk of stillbirth from non-placental causes. With regard to biochemical tests, these researchers included assays performed using any technique and at any threshold used to determine test positivity. They extracted the numbers of true positive, false positive, false negative, and true negative test results from each study; and evaluated risk of bias and applicability using the QUADAS-2 tool. Meta-analyses were performed using the hierarchical summary ROC model to estimate and compare test accuracy.
These researchers included a total of 91 studies that evaluated 7 tests – blood tests for human placental lactogen (hPL), estriol, placental growth factor (PlGF) and uric acid, US-EFW and placental grading and urinary estriol – in a total of 175,426 pregnant women, in which 15,471 pregnancies ended in the birth of a small baby and 740 pregnancies which ended in stillbirth. The quality of included studies was variable with most domains at low risk of bias although 59% of studies were deemed to be of unclear risk of bias for the reference standard domain; 53% of studies were of high concern for applicability due to inclusion of only high- or low-risk women. Using all available data for SGA (86 studies; 159,490 pregnancies involving 15,471 SGA infants), there was evidence of a difference in accuracy (p < 0.0001) between the 7 tests for detecting pregnancies that were SGA at birth. US-EFW was the most accurate test for detecting SGA at birth with a diagnostic odds ratio (DOR) of 21.3 (95% CI: 13.1 to 34.6); hPL was the most accurate biochemical test with a DOR of 4.78 (95% CI: 3.21 to 7.13). In a hypothetical cohort of 1,000 pregnant women, at the median specificity of 0.88 and median prevalence of 19%, EFW, hPL, estriol, urinary estriol, uric acid, PlGF and placental grading will miss 50 (95% CI: 32 to 68), 116 (97 to 133), 124 (108 to 137), 127 (95 to 152), 139 (118 to 154), 144 (118 to 161), and 144 (122 to 161) SGA infants, respectively. For the detection of pregnancies ending in stillbirth (21 studies; 100,687 pregnancies involving 740 stillbirths), in an indirect comparison of the 4 biochemical tests, PlGF was the most accurate test with a DOR of 49.2 (95% CI: 12.7 to 191). In a hypothetical cohort of 1,000 pregnant women, at the median specificity of 0.78 and median prevalence of 1.7%, PlGF, hPL, urinary estriol and uric acid will miss 2 (95% CI: 0 to 4), 4 (2 to 8), 6 (6 to 7) and 8 (3 to 13) stillbirths, respectively. No studies examined the accuracy of US-EFW for detection of pregnancy ending in stillbirth. The authors concluded that biochemical markers of placental dysfunction used alone had insufficient accuracy to identify pregnancies ending in SGA or stillbirth. Studies combining US and placental biomarkers are needed to determine whether this approach improves diagnostic accuracy over the use of US estimation of fetal size or biochemical markers of placental dysfunction used alone. These researchers stated that many of the studies included in this review were performed between 1974 and 2016. Studies of placental substances were mostly carried out before 1991 and after 2013; earlier studies may not reflect developments in test technology. No studies were identified for this review that examined the accuracy of US and blood tests used together.
Routine Third Trimester Ultrasonography to Reduce Adverse Perinatal Outcomes in Low-Risk Pregnancy
In a randomized, multi-center, stepped-wedge cluster trial, Henrichs and colleagues (2019) examined the effectiveness of routine US in the third trimester in reducing adverse perinatal outcomes in low-risk pregnancies compared with usual care and the effect of this policy on maternal outcomes and obstetric interventions. A total of 60 midwifery practices in the Netherlands with 13,046 women aged 16 years or older with a low-risk singleton pregnancy were included in this study. These midwifery practices offered usual care (serial fundal height measurements with clinically indicated US). After 3, 7, and 10 months, 1/3 of the practices were randomized to the intervention strategy. As well as receiving usual care, women in the intervention strategy were offered 2 routine biometry scans at 28 to 30 and 34 to 36 weeks' gestation. The same multi-disciplinary protocol for detecting and managing fetal growth restriction was used in both strategies. The primary outcome measure was a composite of severe adverse perinatal outcomes: perinatal death, Apgar score of less than 4, impaired consciousness, asphyxia, seizures, assisted ventilation, septicemia, meningitis, broncho-pulmonary dysplasia (BPD), intra-ventricular hemorrhage, peri-ventricular leukomalacia, or necrotizing enterocolitis. Secondary outcomes were 2 composite measures of severe maternal morbidity, and spontaneous labor and birth. Between February 1, 2015 and February 29, 2016, 60 midwifery practices enrolled 13,520 women in mid-pregnancy (mean of 22.8 (standard deviation [SD] 2.4) weeks' gestation); 13,046 women (intervention n = 7,067, usual care n = 5,979) with data based on the national Dutch perinatal registry or hospital records were included in the analyses. Small for gestational age (SGA) at birth was significantly more often detected in the intervention group than in the usual care group (179 of 556 (32%) versus 78 of 407 (19%), p < 0.001). The incidence of severe adverse perinatal outcomes was 1.7% (n = 118) for the intervention strategy and 1.8% (n = 106) for usual care. After adjustment for confounders, the difference between the groups was not significant (odds ratio [OR] 0.88, 95% CI: 0.70 to 1.20). The intervention strategy showed a higher incidence of induction of labor (1.16, 1.04 to 1.30) and a lower incidence of augmentation of labor (0.78, 0.71 to 0.85). Maternal outcomes and other obstetric interventions did not differ between the strategies. The authors concluded that in low-risk pregnancies, routine US in the third trimester along with clinically indicated US was associated with higher antenatal detection of SGA fetuses but not with a reduced incidence of severe adverse perinatal outcomes compared with usual care alone. These researchers stated that these findings do not support routine US in the third trimester for low-risk pregnancies. They noted that challenges for future research are to identify the most appropriate fetal growth and birth-weight charts and to develop more sensitive and effective methods to detect fetal growth restriction. Such methods include other US markers of fetal compromise, maternal and placental biomarkers, and maternal awareness of fetal well-being.
The authors stated that this study had strengths and limitations. The cluster randomized design controlled for unknown confounders at the cluster level and limited contamination between the study strategies, which might occur in individual randomized trials. The stepped wedge design reduced confounding owing to differences between midwifery practices because each practice applied the control and intervention strategy for some of the time. Sonographers met pre-defined quality criteria, and a multi-disciplinary protocol was developed for detecting and managing fetal growth restriction to achieve the best quality care possible in a pragmatic nationwide study.
These investigators did not achieve their required sample size of 15,000 women. Owing to the stepped-wedge design, it was not possible to extend the data collection period because the midwifery practices had adopted the intervention strategy at the end of the study period; thus, they could not completely rule out that the study lacked the statistical power to determine if routine US had a beneficial or harmful effect on perinatal outcomes compared with usual care. Although these researchers found a difference of only 0.1% between the 2 strategies, it was unlikely that this difference would have met the pre-defined meaningful difference of 0.54% had the sample size been larger. Also, these researchers used registration data as an initial screening for potential severe adverse perinatal outcomes. Information was also obtained from many hospital records, but for most women only routine registration data for adverse outcomes were available. Because of the inherent limitations of these data, several outcomes might have been mis-classified as normal, resulting in an under-estimation of the primary outcome for both strategies. However, these investigators did not expect that this has biased the comparison between the 2 strategies as the incidence of adverse outcomes was similar to their estimations. Furthermore, because of the collinearity of time of inclusion period and study condition, these investigators were unable to adjust for time. The effect estimates of their main analyses might therefore be over-estimated. Also, this study was conducted in 1 country (the Netherlands) where primary antenatal care of uncomplicated pregnancies is provided by midwives who are educated, trained, and officially registered as independent health practitioners. When risk factors or complications occur, women are referred to obstetrician led care. For about 90% of women in the Netherlands, antenatal care is midwife led initially, and about 50% of women start labor in midwife led care. Also, most of the recommendations of the multi-disciplinary protocol for diagnosing and managing suspected fetal growth restriction in this study were similar to international guidelines in other countries (e.g., the Royal College of Obstetricians and Gynecologist), making these findings relevant to low-risk populations in other international care contexts.
Fetal Ultrasound with Detailed Anatomic Examination for Evaluation of the Fetus of a Mother who has Uterus Didelphys
Malini et al. (1984) conducted a retrospective study involving 68 female patients with sonographic diagnoses of genital tract anomalies. Corroboration through hysterosalpingography and/or surgery was available in 47 cases (69%) and by visualization of two cervices on physical examination in three cases (4%). The scan results were categorized as diagnostic, confirmatory, or incorrect; 50 patients were classified into the following proposed categories: segmental Müllerian agenesis (4 cases), "peculiar appearing" uterus (3 cases), uterus didelphys (19 cases), bicornuate and septate uterus (22 cases), and obstructed lower with a normal upper genital tract (2 cases).
Witters et al. (2012) noted that hydrometrocolpos, which occurs in approximately 1 in 6,000 newborn girls, can result from a stenotic urogenital sinus, a severe cloacal malformation, or other conditions such as an imperforate hymen, a midline vaginal septum, and vaginal atresia. The prenatal differential diagnosis of this wide spectrum of conditions is complex and requires a multidisciplinary approach, including follow-up scans and magnetic resonance imaging (MRI) to assess the severity of the condition. A non-consanguineous couple was referred during their first pregnancy at 30 weeks. The father, a 30-year-old of Caucasian origin, and the mother, a 26-year-old of Asian origin, underwent ultrasound (US) at 30 weeks, which revealed ambiguous genitalia (with suspicion of clitoral hypertrophy), a septated structure located behind the bladder compatible with hydrometrocolpos and a uterine malformation (uterus didelphys), a single umbilical artery, mild ascites, and growth on the 10th centile. The differential diagnosis included vaginal atresia, a urogenital sinus, and a more severe cloacal malformation. After serial scans, MRI, and counseling by an experienced surgeon, the preferred diagnosis of a cloacal malformation was made, leading to a late pregnancy termination. Pathological examination revealed low vaginal atresia with uterus didelphys, anal atresia with rectovaginal fistula, and a normal urinary tract. The differential diagnosis between hydrometrocolpos due to vaginal atresia and that due to a more severe cloacal malformation is not straightforward, necessitating careful decision-making and counseling for patients with these complex prenatal malformations.
In a retrospective cohort study, Crane et al. (2012) examined whether cervical length measured by transvaginal ultrasound (TVUS) in women with uterine anomalies predicts spontaneous preterm birth (SPTB). The researchers compared women with a uterine anomaly who were pregnant with singleton gestations and delivered between August 2000 and April 2008 to a low-risk control group. Transvaginal ultrasonographic cervical lengths were measured between 16 and 30 weeks of gestation. The primary outcome was cervical length and SPTB occurring before 35 weeks, with cervical length as the primary exposure variable of interest. Secondary outcomes included SPTB before 37 weeks, before 32 weeks, low birth weight, and maternal and neonatal outcomes. Receiver operating characteristic curves (ROCs) were generated to identify the best cervical length cut-off. Women with a bicornuate uterus (n = 35) had shorter cervical lengths (3.46 cm) compared to the low-risk control group (n = 122, 4.32 cm, p < 0.0001). Women with a bicornuate or didelphys uterus had higher rates of SPTB before 35 weeks (8.6% and 30.8% versus 0.8%, p = 0.0007), neonatal intensive care unit (NICU) admissions for more than 24 hours (26.5% and 41.7% versus 7.5%, p = 0.0021), and composite perinatal morbidity (32.4% and 69.2% versus 8.3%, p < 0.0001). Using a cut-off of 3.0 cm, TVUS cervical length in women with a bicornuate uterus predicted SPTB before 35 weeks (positive predictive value [PPV] = 37.5% and negative predictive value [NPV] = 100%), birth weight less than 2,500 g (PPV = 50.0% and NPV = 96.3%), and respiratory distress syndrome (PPV = 37.5% and NPV = 100%). The authors concluded that women with a bicornuate uterus had shorter cervical lengths than low-risk controls and were at higher risk of SPTB before 35 weeks; TVUS cervical length predicted SPTB before 35 weeks, low birth weight, and perinatal morbidity in these women.
Hughes et al. (2020) noted that uterine anomalies occur in an estimated 5% of women and are associated with a higher risk of SPTB. A sonographically short cervix (less than 25 mm) is a risk indicator for SPTB, although its predictive utility has been little studied in this specific high-risk population. In a historical cohort study, these researchers examined pregnancy outcomes and the predictive ability of a short cervix in women with uterine anomalies attending a high-risk antenatal clinic. They evaluated all pregnancies in women with congenital uterine anomalies referred to the Preterm Labor Clinic at the Royal Women's Hospital in Melbourne, Australia, between 2004 and 2013. Logistic and linear regressions and ROCs were used to examine associations between cervical length and preterm birth. SPTB (before 37 weeks' gestation) occurred in 23% of the 86 pregnancies (n = 20); rates by subgroup were as follows: unicornuate uterus 60% (n = 3/5), uterus didelphys 40% (n = 6/15), bicornuate uterus 18% (n = 9/51), and septate uterus 13% (n = 2/15). Preterm pre-labor rupture of membranes occurred in 55% of spontaneous preterm births and was not independently associated with the presence of cervical cerclage or ureaplasma urealyticum. A short cervical length was associated with SPTB in women with a septate uterus. A short cervix at 24 weeks (but not at 16 or 20 weeks) was moderately predictive of SPTB before 34 weeks. The authors concluded that women with uterine anomalies are at increased risk of spontaneous preterm birth, especially those with a unicornuate uterus or uterus didelphys, but cervical surveillance did not identify these cases. A short cervix may be associated with SPTB in women with a septate uterus. Preterm pre-labor rupture of membranes occurred in 55% of SPTB cases. Ultrasonography was one of the keywords listed in this study.
Furthermore, an UpToDate review on “Congenital uterine anomalies: Clinical manifestations and diagnosis” (Laufer and DeCherney, 2020) states that “Uterus didelphys, or double uterus, is a duplication of the reproductive structures. Generally, the duplication is limited to the uterus and cervix (uterine didelphys and bicollis [two cervixes]), although duplication of the vulva, bladder, urethra, vagina, and anus may also occur. Fifteen to 20% of patients with a didelphic uterus also have unilateral anomalies, such as an obstructed hemivagina and ipsilateral renal agenesis; the anomalies are on the right in 65% of cases. Uterine didelphys occurs when the two Müllerian ducts fail to fuse. Diagnosis is typically made through a combination of ultrasound showing two widely separated uterine horns with a deep fundal indentation and a speculum examination revealing two cervices. MRI is rarely needed to make a definitive diagnosis.”
Obstetric Anatomic Ultrasound and Fetal Echocardiography in Detecting Congenital Heart Disease in High-Risk Pregnancies
Krishnan and colleagues (2021) examined the concordance between 2nd-trimester anatomic US and fetal echocardiography in detecting minor and critical CHD in pregnancies meeting American Heart Association (AHA) criteria. These investigators carried out a retrospective cohort study of pregnancies in which a 2nd-trimester fetal anatomic US examination (18 to 26 weeks) and fetal echocardiography were conducted between 2012 and 2018 at the authors’ institution based on AHA recommendations. Anatomic US studies were interpreted by maternal-fetal medicine specialists and fetal echocardiographic studies by pediatric cardiologists. The primary outcome was the proportion of critical CHD (CCHD) cases not detected by anatomic US but detected by fetal echocardiography. The secondary outcome was the proportion of total CHD cases missed by anatomic US but detected by fetal echocardiography. Neonatal medical records were reviewed for all pregnancies when obtained and available. A total of 722 studies met inclusion criteria. Anatomic US and fetal echocardiography were in agreement in detecting cardiac abnormalities in 681 (96.1%) studies (κ = 0.803; p < 0.001). The most common diagnosis not identified by anatomic US was a ventricular septal defect, accounting for 9 of 12 (75%) missed congenital heart defects. Of 664 studies with normal cardiac findings on the anatomic US examinations, no additional instances of CCHD were detected by fetal echocardiography. No unanticipated instances of CCHD were diagnosed postnatally. The authors concluded that with current AHA screening guidelines, automatic fetal echocardiography in the setting of normal detailed anatomic US findings provided limited benefit in detecting congenital heart defects that would warrant immediate post-natal interventions. These investigators stated that more selective use of automatic fetal echocardiography in at-risk pregnancies should be explored.
Detailed Fetal US for Diagnosis / Evaluation of Uterus Didelphys
Hughes et al. (2020) noted that uterine anomalies occur in an estimated 5% of women and have been shown to confer a higher risk of spontaneous preterm birth (SPTB). A sonographically short cervix (less than 25 mm) is a risk indicator for SPTB, although its predictive utility has been little studied in this specific high-risk population. In a historical cohort study, these researchers examined the pregnancy outcomes and predictive ability of a short cervix in a cohort of women with uterine anomalies attending a high-risk antenatal clinic. They evaluated all pregnancies in women with congenital uterine anomalies referred to the Preterm Labor Clinic at the Royal Women's Hospital in Melbourne, Australia, between 2004 and 2013. Logistic and linear regressions and receiver operating characteristic (ROC) curves were used to examine associations between cervical length and preterm birth. SPTB (before 37 weeks' gestation) occurred in 23% of the 86 pregnancies (n = 20); rates by subgroup were as follows: unicornuate uterus 60% (n = 3/5), uterus didelphys 40% (n = 6/15), bicornuate uterus 18% (n = 9/51), and septate uterus 13% (n = 2/15). Preterm pre-labor rupture of membranes occurred in 55% of spontaneous preterm births and was not independently associated with the presence of cervical cerclage or ureaplasma urealyticum. A short cervical length was associated with SPTB in women with a septate uterus. A short cervix at 24 weeks (but not at 16 or 20 weeks) was moderately predictive of SPTB before 34 weeks. The authors concluded that women with uterine anomalies were at increased risk of spontaneous preterm birth, especially those with a unicornuate uterus or uterus didelphys, but cervical surveillance did not identify these cases. A short cervix may be associated with SPTB in women with a septate uterus. Preterm pre-labor rupture of membranes occurred in 55% of SPTB cases. Ultrasonography was one of the keywords listed in this study.
Furthermore, an UpToDate review on “Congenital uterine anomalies: Clinical manifestations and diagnosis” (Laufer and DeCherney, 2021) states that “Uterus didelphys, or double uterus, is a duplication of the reproductive structures. Generally, the duplication is limited to the uterus and cervix (uterine didelphys and bicollis [two cervixes]), although duplication of the vulva, bladder, urethra, vagina, and anus may also occur. Fifteen to 20% of patients with a didelphic uterus also have unilateral anomalies, such as an obstructed hemivagina and ipsilateral renal agenesis; the anomalies are on the right in 65% of cases. Uterine didelphys occurs when the two Müllerian ducts fail to fuse. Diagnosis is typically made by a combination of ultrasound showing two widely separated uterine horns with a deep fundal indentation and a speculum examination revealing two cervices. MRI is rarely needed to make a definitive diagnosis.”
Detailed Fetal US at 20 Weeks Based on Previous Pregnancy with a Child with DiGeorge Syndrome
The American Institute of Ultrasound in Medicine (AIUM)’s practice parameter on “Performance of detailed second- and third-trimester diagnostic obstetric ultrasound examinations” (AIUM, 2019) lists “previous fetus or child with a congenital, genetic, or chromosomal abnormality” as an indication for a detailed fetal anatomic examination.
GeneReviews’ webpage on “22q11.2 Deletion syndrome” (McDonald-McGinn et al., 2020) states that a fetus at high risk of having 22q11.2DS should undergo a level II ultrasound with a fetal echocardiogram to evaluate for the following anomalies: congenital heart disease; airway, palate, swallowing, and gastrointestinal (GI) differences possibly leading to polyhydramnios (including congenital diaphragmatic hernia, tracheoesophageal fistula, subglottic stenosis, vascular ring, laryngeal web, cleft palate, and cleft lip/palate); renal anomalies; skeletal differences such as clubfoot and craniosynostosis; and umbilical and inguinal hernias.
Furthermore, an UpToDate review on “Overview of ultrasound examination in obstetrics and gynecology” (Shipp, 2021) states that “Detailed examination — A detailed (or specialized or comprehensive) fetal structural survey should only be undertaken by those with the necessary training and skills required for these advanced examinations. Indications for a detailed fetal examination include, but are not limited to, a previous pregnancy affected by a fetal anatomic or chromosomal abnormality; suspected, including those at increased risk for, or known fetal anatomic or chromosomal abnormality in the current pregnancy; known fetal growth disorder; and current pregnancy complications possibly affecting the fetus (e.g., congenital infection, abnormal amniotic fluid volume, alloimmunization, suspected placenta accreta spectrum). Fetal evaluation in these settings requires a more detailed examination of fetal and placental anatomy than a standard fetal survey and necessitates more advanced skills and knowledge.”
Detailed Fetal Ultrasound for Myasthenia Gravis During Pregnancy
Bansal and colleagues (2018) noted that the management of myasthenia gravis (MG) during pregnancy requires special skills as both diseases as well as its treatment can have deleterious effects on mother and fetus. MG often affects women in 2nd and 3rd decades of life during the child-bearing age. Exacerbations of MG are likely to occur during the 1st trimester and post-partum period. The treatment of MG during pregnancy needs to be individualized depending on the severity of MG as well as the effectiveness of various treatment modalities and their possible harmful effects on pregnancy. Furthermore, special attention has to be given to avoid drugs and other factors (such as urinary tract infections) that may worsen MG. The key to successful outcome during pregnancy in women with MG lies in multi-disciplinary care involving obstetricians, neurologists, anesthetist as well as neonatologist. The authors discussed various therapeutic options available for the management of MG during pregnancy and provided recommendations based on the current best evidence. Detailed fetal US is not mentioned as a management tool.
Furthermore, an UpToDate review on “Management of myasthenia gravis in pregnancy” (Bird et al., 2022) does not mention detailed / 3D fetal ultrasound as a management tool.
Detailed Fetal Ultrasound for Syphilis During Pregnancy
Junior et al. (2012) noted that the number of syphilis cases has been increasing considerably, particularly in Eastern Europe, leading to a higher incidence of congenital syphilis. Some complications of congenital syphilis can be detected through 2D ultrasonography (2DUS), typically manifesting in the second trimester of pregnancy. The most common ultrasonographic signs include hepatosplenomegaly, placentomegaly, and fetal growth restriction, while less frequent occurrences may include intra-hepatic calcifications, ascites, fetal hydrops, and even fetal death. Three-dimensional ultrasonography (3DUS) is a relatively new imaging technique that complements 2DUS and allows for a detailed assessment of fetal surface anatomy. The researchers presented a case of a 21-year-old primigravida diagnosed with congenital syphilis, showing obstetric 2DUS findings of hepatosplenomegaly, ascites, pericardial effusion, and hyper-echogenicity of the cerebral parenchyma. The 3DUS in rendering mode provided a clear assessment of the fetal limbs, particularly the feet, which appeared twisted and lacked some toes. This imaging technique helped the parents better understand the pathological condition and improved prenatal management and neonatal follow-up. The authors concluded that 3DUS could be routinely used for assessing fetal malformations resulting from congenital infections.
Guidelines on sexually transmitted diseases from the Centers for Disease Control and Prevention (2021) state: "When syphilis is diagnosed during the second half of pregnancy, management should include a sonographic fetal evaluation for congenital syphilis. However, this evaluation should not delay therapy. Sonographic signs of fetal or placental syphilis (e.g., hepatomegaly, ascites, hydrops, fetal anemia, or a thickened placenta) indicate a greater risk for fetal treatment failure; cases accompanied by these signs should be managed in consultation with obstetric specialists. A second dose of benzathine penicillin G 2.4 million units IM after the initial dose might be beneficial for fetal treatment in these situations."
An UpToDate review on “Syphilis in pregnancy” (Norwitz and Hicks, 2021) explains: "Fetal infection should be suspected if there are characteristic findings on ultrasound examination after 20 weeks of gestation in a woman with untreated or inadequately treated syphilis. Before 18 to 20 weeks, fetal abnormalities are not usually seen due to fetal immunologic immaturity."
Detailed Fetal Ultrasound for Pregnant Women with a Previous Pregnancy with a Fetus that had Omphalocele
The Consensus Report on “The detailed fetal anatomic ultrasound examination” (Wax et al., 2014) listed “Previous fetus or child with a congenital, genetic, or chromosomal abnormality” as an indication for a detailed fetal anatomic examination.
Detailed Fetal Ultrasound for Evaluation of Septate or Arcuate Uterus
In a prospective study, Kupesic and Kurjak (1998) compared the accuracy of transvaginal ultrasound (TVUS), transvaginal color Doppler, hysterosonography, and 3D ultrasound (3D-US) in detecting septate uteri. They also examined the obstetrical prognosis of the septate uterus and the reproductive outcomes following operative hysteroscopy. A total of 420 infertile patients undergoing hysteroscopy were examined over a four-year period. TVUS and color Doppler were performed on all patients, while hysterosonography and 3D-US were utilized in 76 and 86 patients, respectively. The sensitivity of TVUS and transvaginal color Doppler in identifying the septate uterus was 95.0% and 99.3%, respectively. Color and pulsed Doppler studies of the septal area revealed vascularity in 71.2%. The sensitivity of hysterosonography and 3D-US in detecting the septate uterus was 100% and 93.6%, respectively. However, while 3D-US predicted the existence of a congenital uterine defect in all patients with a septate uterus, it was inaccurate in differentiating it from other fusion anomalies. The pregnancy rate in 116 patients following operative hysteroscopy for an intra-uterine septum during a 24-month follow-up period was 50.9%, with 44 patients (74.6%) achieving term deliveries, 11 (18.6%) experiencing first-trimester abortions, and 4 (6.8%) having pre-term deliveries. The authors concluded that transvaginal color Doppler and hysterosonography were highly accurate diagnostic tools for pre-operative evaluation of uterine cavitary defects, and that 3D-US enhanced the accuracy of conventional 2D transvaginal scans by allowing precise reconstruction of the uterine cavity. They found that removing the intra-uterine septum in patients suffering from infertility and recurrent pregnancy loss was beneficial.
In another prospective study, Heinonen (1999) analyzed 467 births among 255 women with uterine malformations and found that 3 (0.64%) newborns had limb reduction defects; 2 women had a subseptate uterus and 1 had a complete septate uterus with a longitudinal vaginal septum. One newborn had bilateral split hand and split foot, while another had an absence of the left hand and wrist. One infant was born without a left hand, wrist, and 1 antebrachial bone, associated with omphalocele and diaphragmatic hernia, and died during the neonatal period. The author suggested that there might be an association between severe limb reduction defects and septate uterus, although the mechanism remained unclear. The findings indicated a need to examine the uterine cavity if a newborn presented with such defects, and a detailed ultrasound examination of fetal limbs was recommended in cases of pregnant women with a septate uterus.
Woelfer et al. (2001) examined reproductive outcomes in women with congenital uterine anomalies detected incidentally by 3D-US. They studied 1,089 women with no history of infertility or recurrent miscarriage who underwent a TVUS scan, screening for uterine abnormalities using 3D-US. They determined the prevalence of miscarriage and pre-term labor in women with normal and abnormal uterine morphology. Of the participants, 983 had a normally shaped uterine cavity, 72 had an arcuate uterus, 29 had a subseptate uterus, and 5 had a bicornuate uterus. Women with a subseptate uterus had a significantly higher proportion of first-trimester losses (Zeta = 4.68, p < 0.01) compared to those with a normal uterus. Women with an arcuate uterus had a significantly greater proportion of second-trimester losses (Zeta = 5.76, p < 0.01) and pre-term labor (Zeta = 4.1, p < 0.01). No other significant differences in pregnancy outcomes were observed between women with normal and abnormal uterine morphology. The authors concluded that their findings highlighted the potential value of 3D-US and confirmed that women with congenital uterine anomalies were more likely to experience adverse pregnancy outcomes than those with a normal uterus.
Ghi et al. (2012) stated that a septate uterus appeared to be strongly associated with adverse pregnancy outcomes; however, the relationship between septate uterus and miscarriage had only been studied retrospectively. They described the reproductive outcomes in women with incidental diagnoses of malformed uterus during first-trimester scans. Women in their first pregnancy attending the authors’ center for routine viability scans, with incidental suspicion of uterine anomaly at standard ultrasound, underwent TVUS. All cases with a 3D diagnosis of septate uterus were prospectively recruited and followed up. A total of 24 patients with a single intra-uterine pregnancy were included at a median gestational age of 8.2 weeks. The cumulative pregnancy progression rate, as calculated by the Kaplan-Meier algorithm, was 33.3%, with early (≤13 weeks) or late miscarriages (14 to 22 weeks) occurring in 13 and 3 cases, respectively. The authors concluded that pregnancy outcomes were poor when a septate uterus was incidentally diagnosed in the early stages of a viable intra-uterine pregnancy.
Ridout et al. (2019) noted that congenital uterine anomalies are associated with late miscarriage and spontaneous preterm birth (SPTB). In a retrospective cohort study, these researchers determined the rate of SPTB for each type of congenital uterine anomaly and examined the performance of quantitative fetal fibronectin (fFN) and cervical length (CL) measurements by TVUS in asymptomatic women with congenital uterine anomalies for predicting SPTB at less than 34 and less than 37 weeks of gestation. This trial included women with congenital uterine anomalies who were asymptomatic for SPTB, from four tertiary referral centers in the U.K. (2001 to 2016). Congenital uterine anomalies were categorized into fusion (unicornuate, didelphic, and bicornuate uteri) or resorption defects (septate, with or without resection, and arcuate uteri), based on pre-pregnancy diagnosis. All women underwent serial TVUS CL assessments in the second trimester (16 to 24 weeks' gestation), and a subgroup underwent quantitative fFN testing starting at 18 weeks' gestation. The investigators also examined the relationship between congenital uterine anomalies and the predictive test performance for SPTB at less than 34 and less than 37 weeks' gestation. A total of 319 women were identified as having congenital uterine anomalies in this high-risk population. Of these women, 7% (23/319) delivered spontaneously at less than 34 weeks' gestation, and 18% (56/319) at less than 37 weeks' gestation. Rates of SPTB by type were as follows: 26% (7/27) for unicornuate, 21% (7/34) for didelphic, 16% (31/189) for bicornuate, 13% (7/56) for septate, and 31% (4/13) for arcuate. Notably, 80% (45/56) of women who had SPTB at less than 37 weeks did not develop a short CL (less than 25 mm) during the surveillance period (16 to 24 weeks). The diagnostic accuracy of short CL had a low sensitivity (20.3%) for predicting SPTB at less than 34 weeks. Cervical length had an area under the ROC of 0.56 (95% CI: 0.48 to 0.64) and 0.59 (95% CI: 0.55 to 0.64) for predicting SPTB at less than 34 and less than 37 weeks, respectively. The area under the curve for CL to predict SPTB at less than 34 weeks was 0.48 for fusion defects (95% CI: 0.39 to 0.57) but 0.78 (95% CI: 0.66 to 0.91) for women with resorption defects. Overall, quantitative fFN had an area under the curve of 0.63 (95% CI: 0.49 to 0.77) and 0.58 (95% CI: 0.49 to 0.68) for predicting SPTB at less than 34 and less than 37 weeks, respectively. The area under the curve for predicting SPTB at less than 37 weeks with quantitative fFN for fusion defects was 0.52 (95% CI: 0.41 to 0.63) but 0.79 (95% CI: 0.63 to 0.95) for women with resorption defects. Results were similar when women with interventions were excluded. The authors concluded that commonly used markers of CL and quantitative fFN had utility in predicting SPTB in resorption congenital uterine defects but not in fusion defects, which was contrary to findings in other high-risk populations. They stated that these findings need to be considered when planning antenatal care and have potential implications for predictive tests used in SPTB surveillance and intervention.
Hughes et al. (2020) noted that uterine anomalies occur in an estimated 5% of women and have been shown to confer a higher risk of SPTB. A sonographically short cervix (less than 25 mm) is a risk indicator for SPTB, although its predictive utility has been little studied in this specific high-risk population. In a historical cohort study, these researchers examined the pregnancy outcomes and predictive ability of short cervix in a cohort of women with uterine anomalies attending a high-risk antenatal clinic. This trial evaluated all pregnancies in women with congenital uterine anomalies referred to the Preterm Labor Clinic at the Royal Women's Hospital in Melbourne, Australia, between 2004 and 2013. Logistic and linear regressions and ROC analyses were used to examine associations between cervical length and preterm birth. SPTB (less than 37 weeks' gestation) occurred in 23% of the 86 pregnancies (n = 20); rates by subgroup were as follows: unicornuate uterus 60% (n = 3/5), uterus didelphys 40% (n = 6/15), bicornuate uterus 18% (n = 9/51), and septate uterus 13% (n = 2/15). Preterm premature rupture of membranes (PPROM) occurred in 55% of SPTBs and was not independently associated with the presence of cervical cerclage or ureaplasma urealyticum. A short cervical length was associated with SPTB in women with a septate uterus. A short cervix at 24 weeks (but not at 16 or 20 weeks) was moderately predictive of SPTB at less than 34 weeks. The authors concluded that women with uterine anomalies were at increased risk of SPTB, especially those with a unicornuate uterus or uterus didelphys; however, cervical surveillance did not identify these cases. They noted that a short cervix may be associated with SPTB in women with a septate uterus, and that PPROMs occurred in 55% of SPTB cases. The authors emphasized the need for further research to examine the etiology of SPTB to help determine appropriate monitoring and treatment.
In a prospective cohort study, Negm et al. (2022) examined the reliability of 3D-US in differentiating between subseptate and arcuate uteri due to the different associated pregnancy outcomes. They refined existing 3D-US parameters and assessed the concordance between 3D-US and MRI in diagnosing these anomalies. This trial enrolled 455 women suspected of having a Müllerian anomaly. The diagnosis of subseptate, bicornuate, or arcuate uterus was made by 3D-US in 55 women. Two independent examiners manipulated the 3D-US volume datasets and recorded the internal inter-cornual distance, indentation length, indentation tip angle, and myometrial wall thickness in the coronal plane of the uterus. Subsequently, 48 women underwent MRI, which served as the reference test for diagnosis. The investigators calculated the degree of correlation between the two US assessors' 3D-US measurements using inter-class correlation coefficients and a Bland-Altman plot. The mean values of the four parameters were used to create ROC curves for determining the best cut-off values for differentiating between subseptate and arcuate uteri. They used Cohen's Kappa test to measure the level of agreement between 3D-US and MRI. There was good inter-observer agreement between the two 3D-US assessors for all four parameters. A substantial level of agreement was found between 3D-US and MRI in differentiating between bicornuate, subseptate, and arcuate uteri, with a kappa value of 0.727 (95% CI: 0.443 to 0.856). Distinction between subseptate and arcuate uterus was improved when using an indentation length of greater than or equal to 12.5 mm (AUC 0.99) and an indentation tip angle of less than or equal to 89.25 degrees (AUC 0.97) as cut-offs for diagnosis, but not for the internal inter-cornual distance or myometrial wall thickness. The authors concluded that 3D-US evaluation of the coronal view of the uterus could be relied upon to make a non-invasive, accurate differentiation between subseptate and arcuate uteri. The fundal indentation length and indentation tip angle cut-offs of greater than or equal to 12.5 mm and less than or equal to 89.25 degrees, respectively, were found to be the most accurate for distinction, allowing for individualized pre-pregnancy management plans and patient-informed healthcare choices. They noted that there were no agreed-upon criteria for differentiating arcuate from subseptate uteri, which was critical for counseling and management due to the substantial differences in pregnancy outcomes. The authors aimed to propose cut-off values for US measurements standardized against MRI diagnostic criteria for accurate differentiation between arcuate and subseptate uteri, demonstrating substantial agreement between 3D-US and MRI in differentiating between these anomalies.
An UpToDate review on “Congenital uterine anomalies: Clinical manifestations and diagnosis” (Laufer and DeCherney, 2022) states that “In a literature review of studies including infertile and fertile patients with congenital uterine anomalies (CUAs), the frequencies of specific anomalies were: septate (35%), bicornuate (26%), arcuate (18%), unicornuate (10%), didelphys (8%), and agenesis (3%). However, these frequencies can vary substantially depending on the specific population studied and the methodology used to identify the abnormalities. In a well-designed study of patients with normal reproductive outcomes described above, the frequencies were: septate (90%), bicornuate (5%), and didelphic (5%). Most patients undergo 2D-US examination as the initial imaging modality, which also provides information about relevant non-uterine structures (e.g., ovaries, kidneys). 3D-US is helpful for assessing the outer contour of the fundus (i.e., differentiating between a septate and a bicornuate uterus). Hysterosalpingography provides information about fallopian tube patency and the size and configuration of the uterine cavity or cavities. Saline infusion sonohysterography and hysterosalpingography both delineate the uterine cavity well.”
Furthermore, the Consensus Report on “The detailed fetal anatomic ultrasound examination” (Wax et al., 2014) did not list “septate or arcuate uterus” as indications for a detailed fetal anatomic examination.
Detailed Fetal Ultrasound for Hypo-Coiled / Hyper-Coiled Umbilical Cord
In a prospective study, Verkleij et al. (2013) examined the association between ultrasound-assessed hyper- or hypo-coiling of the umbilical cord and the presence of trisomy 21. The study aimed to provide reference values for the antenatal umbilical coiling index (aUCI) at a gestational age of 16 to 21 weeks and to assess the reliability and reproducibility of these measurements. The study included 737 pregnancies in which the aUCI was measured via ultrasound at the time of amniocentesis. The aUCI was calculated as the reciprocal value of the mean length (in cm) of one complete coil. The researchers created reference curves and studied the relationship between aUCI and trisomy 21 as well as other chromosomal defects. In 30 pregnancies, they examined intra- and inter-observer variation in measurements using Bland-Altman plots with associated 95% confidence intervals and intra-class correlation coefficients. The aUCI was found to be non-linearly related to gestational age at 16 to 21 weeks, and reference curves were established for the mean aUCI and the 2.3rd, 10th, 90th, and 97.7th percentiles. There was no significant difference in aUCI values between the reference group (n = 714) and cases with trisomy 21 (n = 16) or other aneuploidies (n = 7) (one-way ANOVA, p = 0.716). The study demonstrated good intra- and inter-observer agreement in aUCI measurements. The authors concluded that the aUCI could be measured reliably and varied according to gestational age at 16 to 21 weeks, but it was not significantly associated with trisomy 21 or other chromosomal defects.
In a systematic review, Jessop et al. (2014) determined the frequency of pre-defined clinical outcomes in relation to umbilical cord coiling indices greater than the 90th percentile and less than the 10th percentile in an unselected population of over 1,000 women with singleton pregnancies resulting in live births at or near term. The study included placentas from consecutive deliveries in a low-risk population with umbilical cords longer than 15 cm. Clinical outcomes assessed included interventional delivery, birth weight of less than the 10th percentile, Apgar scores of less than 7 at 1 minute, neonatal acidosis (pH of less than 7.2), and admission to neonatal special care. The systematic review adhered to standard MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines. Umbilical coiling index (UCI) was determined for 1,082 placentas. The mean maternal age was 30.7 years (SD = 5.7), and 519 women (48%) were primiparous. The mean cord length was 43 cm (SD = 13), and the mean cord coiling index was 0.20 (SD = 0.09). A total of 866 cords were normally coiled, while 108 cases were hyper-coiled (greater than the 90th percentile) and 108 cases were under-coiled (less than the 10th percentile). There were no differences in clinical outcomes between cases of over-coiled, normally coiled, or under-coiled cords. The systematic review yielded a small number of clinical studies that were too statistically and clinically heterogeneous to allow for meta-analysis. The authors concluded that there was insufficient evidence from this unselected cohort study or from the systematic review to support the previous suggestion that UCI greater than the 90th percentile or less than the 10th percentile was associated with adverse clinical outcomes in an unselected population. Previous studies linking abnormal cord coiling to clinical outcomes were generally too small and/or selective to allow for meaningful conclusions applicable to low-risk populations.
In a cross-sectional study, Sharma et al. (2018) examined the relationship between aUCI measured at 18 to 20 weeks along with level-II ultrasound and adverse perinatal outcomes. This trial involved 408 antenatal women enrolled at the time of fetal anatomic survey, with their aUCI measured and its association with perinatal outcomes observed. UCI was classified as hypo-coiled if it was less than the 10th percentile, hyper-coiled if it was greater than the 90th percentile, and normo-coiled if it was between the 10th and 90th percentiles. The mean aUCI was 0.43 ± 0.30 (normo-coiled group), 0.18 ± 0.4 (hypo-coiled), and 0.53 ± 0.05 (hyper-coiled group). The average gestational age at delivery in the hypo-coiled group was 36.8 ± 2.34 weeks, which was shorter than the 38.3 ± 1.82 weeks in the normo-coiled group and 38.9 ± 1.72 weeks in the hyper-coiled group. Mean birth weights observed were 2,055 ± 744 g (hypo-coiled group), 3,049 ± 564 g (hyper-coiled), and 3,102 ± 564 g (normo-coiled); p < 0.001. Preterm births (PTBs) and low birth weights were significantly associated with hypo-coiling (52 cases, 59% and 76 cases, 69%, respectively). The authors concluded that abnormal UCI detected at the fetal ultrasound anatomic survey in the second trimester (18 to 20 weeks) could potentially serve as a screening or predictive tool for adverse antenatal or perinatal events.
Krzyzanowski et al. (2019) emphasized the importance of examining umbilical cord anatomy during the first trimester ultrasound examination. They noted the necessity of confirming the correct number of umbilical vessels and their intra-abdominal course, as well as carefully evaluating the abdominal and placental insertion sites. In the latter half of pregnancy, Doppler imaging enables the evaluation of the function of fetal-placental vessels, providing valuable information regarding fetal condition. The researchers stated that the detection of a single umbilical artery (SUA) during prenatal examinations should prompt a detailed ultrasound assessment of all organs and systems.
In a meta-analysis and sequential analysis, Pergialiotis et al. (2020) examined the potential association of abnormal cord coiling with adverse pregnancy outcomes. They utilized multiple databases, including Medline, Scopus, Clinicaltrials.gov, Embase, Cochrane Central Register of Controlled Trials, and Google Scholar, with the last search conducted on May 31, 2018. No language, country, or date restrictions were applied to prevent bias. All observational studies reporting maternal and neonatal antenatal and perinatal outcomes based on UCI status were included. Meta-analysis of the relative risk (RR) and mean difference (MD) among hypo-coiled/hyper-coiled and normo-coiled cases was performed using RevMan 5.3 software. Univariate meta-regression and leave-one-out meta-analysis were conducted with Open Meta-Analyst statistical software, and trial sequential analysis was performed with TSA software. A total of 24 studies involving 9,553 pregnant women were included. Umbilical cord coiling was examined using the UCI, with values below the 10th percentile deemed hypo-coiled and above the 90th percentile as hyper-coiled. Hypo-coiled cords were significantly associated with increased prevalence of preterm birth (PTB) of less than 37 weeks, the need for interventional delivery due to fetal distress, meconium-stained liquor, Apgar scores of less than 7 at 5 minutes, small for gestational age (SGA) neonates, fetal anomalies, NICU admissions, fetal heart rate abnormalities, and fetal death. Hyper-coiled cords were also significantly associated with increased prevalence of PTB of less than 37 weeks, interventional delivery due to fetal distress, meconium-stained liquor, Apgar scores of less than 7 at 5 minutes, SGA neonates, fetal anomalies, fetal growth restriction, fetal heart rate abnormalities, fetal acidosis, and fetal death. The authors concluded that the findings of this meta-analysis highlighted the correlation between UCI abnormalities and antenatal and perinatal pathology. They stated that further studies are needed to determine whether antenatal assessment of the UCI could be routinely used in clinical practice and to evaluate its value in uncomplicated pregnancies.
Hayes et al. (2020) noted that current data on the role of the umbilical cord in pregnancy complications are conflicting, with estimates of the proportion of stillbirths due to cord problems ranging from 3.4% to 26.7%. In a systematic review and meta-analysis, these investigators aimed to determine which umbilical cord abnormalities are associated with stillbirth and related adverse pregnancy outcomes. They searched Medline, Embase, CINAHL, and Google Scholar from 1960 to the present day, as well as reference lists of included studies and grey literature. Cohort, cross-sectional, or case-control studies of singleton pregnancies after 20 weeks' gestation that reported the frequency of umbilical cord characteristics or abnormalities and their relationship to stillbirth or other adverse outcomes were included. The quality of included studies was assessed using NIH quality assessment tools, and analyses were performed in STATA. This review included 145 studies. Nuchal cords were present in 22% of births (95% CI: 19 to 25), multiple loops of cord were present in 4% (95% CI: 3 to 5), and true knots of the cord in 1% (95% CI: 0 to 1) of births. There was no evidence of an association between stillbirth and any nuchal cord (OR 1.11, 95% CI: 0.62 to 1.98). Comparing multiple loops of nuchal cord to single loops or no loop yielded an OR of 2.36 (95% CI: 0.99 to 5.62). The researchers were unable to examine the effect of tight or loose nuchal loops. The likelihood of stillbirth was significantly higher with a true cord knot (OR 4.65, 95% CI: 2.09 to 10.37). The authors concluded that this systematic review and meta-analysis demonstrated links between umbilical cord abnormalities (UCA) and several adverse pregnancy outcomes, although not all analyses were adequately powered, and some comparisons were restricted by the methodologies of the original studies. They stated that further studies are needed to allow robust clinical recommendations on the management of UCA to be made. These studies should utilize the information presented regarding normal cord characteristics to inform thresholds for abnormalities and examine multiple UCA in relation to a range of adverse perinatal outcomes. Ideally, UCA should also be recorded antenatally in blinded studies to calculate prognostic accuracy. Until such data are available, clinicians should be cautious about assigning causality of an adverse outcome based on isolated observations of UCA.
Furthermore, the Consensus Report on “The detailed fetal anatomic ultrasound examination” (Wax et al., 2014) did not list “hypo-coiled/hyper-coiled umbilical cord” as indications for a detailed fetal anatomic examination.
Detailed Fetal Ultrasound for McCune-Albright syndrome
Gaspari et al. (2012) noted that beyond the classic triad of peripheral precocious puberty, café-au-lait skin pigmentation and polyostotic fibrous dysplasia, partial presentation McCune-Albright syndrome (MAS) has been reported, including the association of isolated recurrent ovarian cysts in early infancy. These researchers examined if isolated voluminous fetal unilateral ovarian cysts (diameter of greater than 4 cm) may be associated with a Gsα activating mutation, suggestive of MAS. They followed 5 female fetuses presenting with voluminous unilateral ovarian cysts by ultrasonography (US) until delivery. At birth, all patients underwent percutaneous cyst aspiration; and 2 patients later underwent ovariectomy. A sensitive polymerase chain reaction (PCR)-based method was used to analyze the Gsα activating mutation in DNA obtained from ovarian cystic fluids or tissue. Among the 5 cases, 1 Gsα mutation (R201C) was identified in the ovarian tissue. The authors demonstrated for the 1st time that voluminous fetal unilateral ovarian cysts may be suggestive of MAS. Systematic search for the Gsα mutation should be carried out in all newborns with voluminous fetal unilateral ovarian cysts requiring percutaneous cyst aspiration, because early diagnosis of MAS prevents unnecessary oophorectomy to eliminate questions of malignancy and imposes long-term clinical, biological, and imaging follow-up to detect other early manifestations of MAS. Detailed fetal US was not mentioned as a management tool.
Furthermore, an UpToDate review on “Definition, etiology, and evaluation of precocious puberty” (Harrington and Palmert, 2022) does not mention detailed fetal US as a management option.
Detailed Fetal Ultrasound for Placental Cord Insertion
In a retrospective case-control study, Sinkin et al. (2018) examined perinatal outcomes in singleton and twin pregnancies with pathologically confirmed velamentous cord insertion (VCI) without vasa previa (VP). The study included all non-anomalous singleton and twin pregnancies with pathologically confirmed VCI delivered at a single center between January 1, 2005, and July 1, 2015, and having undergone an ultrasound examination by maternal-fetal medicine. For each case, the next two consecutive deliveries matched for gestational age at delivery ± 1 week, and in twins, amnionicity and chorionicity served as controls. Primary outcomes included surgical delivery for a non-reassuring intra-partum fetal heart rate (HR) tracing, umbilical arterial cord pH of less than 7.2, 5-minute Apgar score of less than 7, birth weight below the 10th percentile, neonatal intensive care unit (NICU) admission, fetal or neonatal death, and cord avulsion necessitating manual placental extraction. Outcomes were available for 53 singletons with 103 matched controls and 33 twin pregnancies with 65 matched controls. In singletons, VCI was associated with a cord pH of less than 7.2 (OR 3.5; 95% CI: 1.1 to 11.2; p = 0.039), a 5-minute Apgar score of less than 7 (OR 5.3; 95% CI: 0.99 to 28.1; p = 0.045), and cord avulsion requiring manual placental extraction (7.5% versus 0%; p = 0.012). Associations were suggested with increased surgical delivery for a non-reassuring intra-partum fetal HR tracing (OR 2.4; 95% CI: 0.9 to 6.9; p = 0.14), birth weight below the 10th percentile (OR 2.1; 95% CI: 0.8 to 5.9; p = 0.21), and fetal or neonatal death (3.8% versus 0%; p = 0.11). VCIs were also associated with placental abruption in singletons (7.5% versus 0%; p = 0.013). Among twins, VCI was associated with fetal or neonatal death (9.1% versus 0%; p = 0.036). The authors concluded that isolated confirmed VCI was associated with adverse perinatal outcomes in both singleton and twin gestations.
However, the researchers noted that this study could not address whether ante-partum fetal surveillance or modifications to ante-partum and intra-partum care could reduce the frequency of VCI-associated adverse outcomes. They emphasized the need for further research specifically addressing these questions. Approximately 1/4 to 1/3 of VCIs are prenatally diagnosed by ultrasound, although detection may be hampered when the placenta is located posteriorly in twins. The investigators called for further research to develop uniform, accurate, and reproducible ultrasound criteria for diagnosing VCI and imaging protocols that allow for consistent, accurate, and reliable characterization of placental cord insertion, as well as to determine the best care strategies for pregnancies with identified VCI.
Buchanan-Hughes et al. (2020) described VCI as an umbilical cord attachment to the membranes surrounding the placenta rather than the central mass. VCI is strongly associated with VP, where umbilical vessels lie in close proximity to the internal cervical os, leaving the vessels vulnerable to rupture and potentially resulting in fatal fetal exsanguination. Screening for VP using second-trimester trans-abdominal sonography (TAS) to detect VCI has been proposed. The researchers conducted a rapid review examining the quality, quantity, and direction of evidence available on the epidemiology, screening test accuracy, and post-screening management pathways for VCI. They searched Medline, Embase, and the Cochrane Library on July 5, 2016, and again on October 11, 2019, using general search terms for VP and VCI. Only peer-reviewed studies reporting on the epidemiology of VCI, the accuracy of the screening test, and/or downstream management pathways for VCI pregnancies were included. The quality and risk of bias of each included study were assessed using pre-specified tools. A total of 41 relevant publications were identified; all but one were based on non-U.K. pregnancy cohorts, and most included relatively few VCI cases. The estimated incidence of VCI was found to be between 0.4% and 11% in singleton pregnancies, with a higher incidence in twin pregnancies (1.6% to 40%). VCI incidence was also increased among pregnancies with one or more other risk factors, including IVF pregnancies or nulliparity. The incidence of VCI among women without any known risk factors was unclear. VCI was associated with adverse perinatal outcomes, most notably pre-term birth (PTB) and emergency cesarean section in singleton pregnancies, and perinatal mortality in twins; however, associations varied across studies, and the increased risk was typically low or moderate compared to pregnancies without VCI. In studies with limited numbers of cases, screening for VCI using TAS demonstrated good overall accuracy, driven by high specificity. No studies on post-screening management of VCI were identified. The authors concluded that the evidence on VCI epidemiology and outcomes is limited and of low quality. They stated that the accuracy of second-trimester TAS and the benefits and harms of screening could not be determined without prospective studies in large cohorts.
The researchers highlighted that the accuracy of the test for VCI has not been well established, and no management pathway is available for women with VCI detected by screening, nor for those with marginal cord insertion (MCI) who would also be detected if screening were implemented. These limitations affected the strength of the evidence needed to inform a U.K. National Screening Committee (NSC) recommendation in this area. They suggested that further meta-analyses on a wider range of outcomes in subgroups of the pregnant population may help examine the level of risk from VCI more thoroughly. However, well-designed prospective studies in larger cohorts of women are needed to produce more robust estimates of VCI incidence and risks, test accuracy, and the practicality of second-trimester testing for VCI. Additionally, modeling studies may be the first step toward understanding whether such studies would be achievable and valuable.
In a retrospective study, Liu et al. (2022) examined the feasibility and accuracy of trans-abdominal color Doppler ultrasound (TA-CDUS) and trans-vaginal color Doppler ultrasound (TV-CDUS) as screening methods for pregnant women with VP and VCI. This trial involved 5,434 pregnant women from 2018 to 2021 who underwent both TA-CDUS and TV-CDUS. The diagnostic performance of TA-CDUS and TV-CDUS was determined using specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy, and positive and negative likelihood ratios (LR+ and LR-), using delivery information (gross examination) as the "gold standard." Patient records were reviewed for demographics and diagnosis. The combination of VP and VCI was diagnosed in 37 out of 5,434 (0.68%) women at delivery. The sensitivity, specificity, PPV, NPV, and overall test accuracy of TA-CDUS were 72.97%, 99.85%, 77.14%, 99.81%, and 99.67%, respectively, for diagnosing VP with VCI. The corresponding values for TV-CDUS were 89.19%, 99.87%, 82.50%, 99.93%, and 99.80%, respectively. Moreover, the sensitivity of the combination of TA-CDUS and TV-CDUS in determining VP with VCI was 97.30%, specificity 99.98%, PPV 97.30%, NPV 99.98%, and accuracy 99.96%. No significant difference in misdiagnosis and missed diagnosis was found between the examinations by TA-CDUS and TV-CDUS. The authors concluded that both TA-CDUS and TV-CDUS could be acceptable diagnostic tools for assessing pregnant women with VP and VCI, with TV-CDUS demonstrating higher accuracy. Furthermore, the combination of TA-CDUS and TV-CDUS could provide an objective imaging basis for choosing clinical treatment strategies and predicting prognosis. However, detailed ultrasound fetal anatomic examination was not mentioned as a management option.
Bohilțea et al. (2022) stated that umbilical cord abnormalities are not rare and are often associated with structural or chromosomal abnormalities, fetal intrauterine growth restriction (IUGR), and poor pregnancy outcomes. These outcomes could result from prematurity, placentation deficiency, or an increased rate of cesarean delivery due to fetal distress, higher NICU admissions, and increased prenatal mortality rates. Even though the incidence of velamentous insertion, VP, and umbilical knots is low, these conditions increase fetal morbidity and mortality both prenatally and intrapartum. The investigators noted a vast heterogeneity among societies' guidelines regarding umbilical cord examination. They advocated for the mandatory introduction of placental cord insertion examination in the first and second trimesters into practice guidelines for fetal ultrasound scans. Additionally, during the mid-trimester scan, they recommended a trans-vaginal ultrasound and color Doppler assessment of the internal cervical os for low-lying placentas, marginal or velamentous cord insertion, and evaluation of umbilical cord entanglement between the insertion sites whenever it is incidentally found. The authors also recommended a detailed fetal anatomical survey for single umbilical artery (SUA)/umbilical artery hypoplasia and umbilical cord cysts/tumors.
Detailed Ultrasound Fetal Anatomic Examination for Patients with New Diagnosis of HIV
Brogly et al. (2010) stated that several studies have detected associations between in-utero anti-retroviral therapy (ARV) exposure and birth defects; however, the evidence remains inconclusive. In this study, a total of 2,202 HIV-exposed children enrolled in the Pediatric AIDS Clinical Trials Group 219 and 219C protocols before 1 year of age were included. Birth defects were classified using the Metropolitan Atlanta Congenital Defects Program (MACDP) coding. Logistic regression models were employed to examine associations between first-trimester in-utero ARV exposure and birth defects. A total of 117 live-born children had birth defects, resulting in a prevalence of 5.3% (95% CI: 4.4 to 6.3). The prevalence did not differ by HIV infection status or overall ARV exposure; rates were 4.8% (95% CI: 3.7 to 6.1) in children without first-trimester ARV exposure and 5.8% (95% CI: 4.2 to 7.8) in those with exposure. The defect rate was notably higher among children with first-trimester efavirenz exposure (5/32, 15.6%) compared to those without (adjusted odds ratio [aOR] = 4.31; 95% CI: 1.56 to 11.86). Protective effects of first-trimester zidovudine exposure on musculoskeletal defects were observed (aOR = 0.24; 95% CI: 0.08 to 0.69), while a higher risk of heart defects was identified (aOR = 2.04; 95% CI: 1.03 to 4.05). The authors concluded that the prevalence of birth defects was higher in this cohort of HIV-exposed children than in other pediatric cohorts. While there was no association with overall ARV exposure, specific agents, including efavirenz, showed some associations. They emphasized the need for additional studies to rule out confounding factors and to examine newer ARV agents.
Williams et al. (2015) noted that most studies examining the association of prenatal ARV exposures with congenital anomalies (CAs) in children born to HIV-infected women have been reassuring; however, some studies suggested an increased risk with specific ARVs. In a prospective cohort multi-center study (the Pediatric HIV/AIDS Cohort Study [PHACS] Surveillance Monitoring of ART Toxicities [SMARTT] Trial), these investigators examined associations of in-utero ARV exposures with CAs in HIV-exposed uninfected children. A total of 2,580 HIV-exposed, uninfected children were enrolled in the SMARTT Trial across 22 U.S. medical centers between 2007 and 2012, experiencing first-trimester exposure to any ARV and to specific anti-retroviral medications. The primary endpoint was a CA, based on clinician review of infant physical examinations according to the Antiretroviral Pregnancy Registry modification of the MACDP. Rates of CAs were estimated overall and by birth year. Logistic regression models were used to examine associations of CAs with first-trimester ARV exposures, adjusting for demographic and maternal characteristics. CAs occurred in 175 of 2,580 children, yielding a prevalence of 6.78% (95% CI: 5.85% to 7.82%); there were 242 confirmed major CAs (72 musculoskeletal, 55 cardiovascular). The prevalence of CAs increased significantly in successive birth cohorts (3.8% for children born before 2002 up to 8.3% for children born between 2008 and 2010). In adjusted models, there was no association of first-trimester exposures to any ARV, combination ARV regimens, or any drug class with CAs. No individual anti-retroviral in the reverse transcriptase inhibitor drug classes was associated with an increased risk of CAs. Among protease inhibitors, higher odds of CAs were observed for atazanavir (aOR = 1.93; 95% CI: 1.23 to 3.03) and for ritonavir used as a booster (aOR = 1.52; 95% CI: 1.08 to 2.14). With first-trimester atazanavir exposure, risks were highest for skin and musculoskeletal CAs (aORs = 5.24 and 2.55, respectively). The authors concluded that few individual ARVs and no drug classes were associated with an increased risk of CAs following adjustment for calendar year and maternal characteristics. While the overall risk remained low, there was a relative increase in successive years and with atazanavir exposure. They asserted that given the low absolute CA risk, the benefits of recommended ARV use during pregnancy still outweigh such risks, although further studies are needed.
Furthermore, the Centers for Disease Control and Prevention (CDC) webpage on “Risk for Neural Tube Defects among Pregnancies of Women with HIV” (CDC, last reviewed: January 9, 2020) states that “Linking data from birth defects and HIV/AIDS programs, scientists found that the risk for neural tube defects among pregnancies of women diagnosed with HIV is similar to that of the general U.S. population. About 1 in every 1,250 babies is born with a neural tube defect each year in the United States.”
Tukei et al. (2021) stated that without treatment, HIV infection in pregnant women is associated with adverse pregnancy outcomes. These researchers compared adverse pregnancy outcomes among HIV-positive women on ARV therapy and HIV-negative women who enrolled for antenatal care in selected health facilities in Maseru district, Lesotho. They enrolled a cohort of HIV-positive and HIV-negative women at their first antenatal visit and followed them through delivery. Study data on miscarriage, stillbirth, preterm birth (PTB), low birth weight, and birth defects were collected through participant interviews and medical record abstraction. The researchers used the Rao-Scott χ² test and the t-test to examine differences in characteristics and outcomes between HIV-positive and HIV-negative women, employing generalized estimating equations for multivariable analysis. A total of 614 HIV-positive and 390 HIV-negative pregnant women were enrolled in the study, with delivery information available for 571 (93.1%) and 352 (90.3%) respectively. In the delivery cohort, the median age at enrollment was 28 years for HIV-positive women and 23 years for HIV-negative women, with median gestational ages of 20 and 21 weeks, respectively. A total of 149 singleton pregnancies had documented adverse pregnancy outcomes—33 (9.6%) in HIV-negative pregnancies and 116 (20.6%) in HIV-positive pregnancies. Compared with their HIV-negative counterparts, HIV-positive women were more likely to experience an adverse pregnancy outcome (aOR = 2.6; 95% CI: 1.71 to 3.97), an intrauterine death (miscarriage or stillbirth) (aOR = 2.64; 95% CI: 1.25 to 5.49), or a low birth weight delivery (aOR = 1.89; 95% CI: 1.16 to 3.09). The authors concluded that adverse pregnancy outcomes remained 2 to 3 times higher among HIV-positive women compared with HIV-negative women despite universal ARV therapy. They also noted that the lack of association of maternal ARV with birth defects observed in this trial was consistent with findings from other studies, as well as the Antiretroviral Pregnancy Registry, confirming the safety of efavirenz-based ARV regimens used in this cohort of women. While the lack of association between this regimen and birth defects is reassuring, the authors emphasized the need for continued pharmacovigilance as countries transition from efavirenz to dolutegravir-based regimens to monitor for adverse outcomes
Klippel-Trenaunay Syndrome
Harnarayan and Harnanan (2022) noted that the Klippel-Trenaunay syndrome (KTS) is an unusual syndrome of vascular and dermatologic manifestation in which patients exhibit hemi-hypertrophy of the soft tissue and bones of one limb, cutaneous hemangiomas and varicosities in anatomically abnormal positions. Described in 1900 by 2 French physicians, the etiology remained unclear until recently, when evidence emerged that there was a genetic basis for this sporadic disorder. Genes that encoded pathological angiogenic factors and caused vascular dysmorphogenesis, explaining the molecular bases of this syndrome, were identified. Several angiogenic genes were identified but 1 gene, the AGGF1 (formerly VG5Q) gene, was observed in mutations involving patients diagnosed with KTS. In addition, KTS was also noted to have overlapping clinical features linked with the “overgrowth syndromes”, in which genetic mutations along somatic lines were identified. These involved the PI3K enzyme that forms part of the phosphoinositide 3-kinase pathway which is encoded by the PIK3CA-gene. This enzyme mediates embryonic cellular growth in-utero; and diseases involved in this pathway are classified as members of the PIK3CA-related overgrowth syndrome. These investigators examined the status of what is now known regarding the molecular genetics of this unusual, but clinically challenging disorder and its differentiation from similar diseases, linked with the PIK3CA-gene and the related overgrowth syndromes.
In-Vitro Fertilization
Larcher et al. (2023) noted that placental anomalies could affect fetal and maternal outcome due to severe maternal hemorrhage potentially resulting in hysterectomy and cord accident including abruption that can lead to fetal damage or death. In a prospective, 2-tertiary center study, these researchers examined if the rate of placental and umbilical cord anomalies are more common in IVF singleton pregnancies compared to spontaneous pregnancies; assessed the role of US in screening for these anomalies and examined if oocyte donor fertilization is an additional risk factor for the development of these anomalies. Patients with a singleton pregnancy conceived with IVF and patients presenting with a spontaneous conception were recruited between May 1, 2019 to March 31, 2021. A total of 634 pregnancies were enrolled in the study. All subjects underwent similar antenatal care, which included US examinations at 11 to 14, 19 to 22 and 33 to 35 weeks. Ultrasound findings of placental and/or umbilical cord abnormalities were recorded using the same protocol for both groups and confirmed after birth. IVF pregnancies had a significantly higher risk of low-lying placenta, placenta previa, bilobed placenta and velamentous cord insertion (VCI) compared with spontaneous pregnancies. In the heterologous subgroup there was a significant increased incidence of placenta accreta spectrum (PAS) disorders than in spontaneous pregnancies. All these anomalies were identified prenatally on US imaging and confirmed at birth. The authors concluded that IVF pregnancies in general and those resulting from donor oocyte in particular were at higher risk of placental and umbilical cord abnormalities compared to spontaneous pregnancies. These anomalies could be diagnosed accurately at the mid-trimester detailed fetal anomaly scan and these findings supported the need for a targeted US screening of these anomalies in IVF pregnancies.
Treatment with Belimumab (Benlysta)
The Prescribing Information (PI) of belimumab (Benlysta) notes that available data on use of Benlysta in pregnant women, from observational studies, published case reports, and post-marketing surveillance, are insufficient to determine whether there is a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with systemic lupus erythematosus (SLE). Monoclonal antibodies, such as belimumab, are actively transported across the placenta during the 3rd trimester of pregnancy and may affect immune response in the in utero-exposed infant. In an animal combined embryo-fetal and pre- and post-natal development study with monkeys that received belimumab by intravenous (IV) administration, there was no evidence of fetal harm with exposures approximately 9 times (based on IV administration) and 20 times (based on subcutaneous administration) the exposure at the maximum recommended human dose (MRHD). Moreover, the PI does not mention the use of fetal US during pregnancy.
Family History of Congenital Heart Defect
Furthermore, an UpToDate review on “Tetralogy of Fallot (TOF): Management and outcome” (Doyle and Kavanaugh-McHugh, 2024) does not mention detailed fetal US as a management option.
Klippel-Trenaunay Syndrome
Ivanitskaya et al. (2020) stated that Klippel-Trenaunay syndrome (KTS) is a rare disease characterized by a classic triad of port wine stains, varicose veins, and bony and soft tissue hypertrophy of an extremity. Other anomalies reported include cavernous hemangiomas, which may involve any region of the body (especially limbs and trunk) and any organ (particularly the lungs, large bowel, bladder, and liver). Anomalies of digits and visceromegaly are also observed. The etiology of KTS remains unknown, and in most cases, it occurs sporadically without a sex predilection. The prognosis of KTS is usually favorable; however, the quality of life (QOL) is significantly affected. Prenatal diagnosis of this syndrome allows for timely determination of the place of delivery and anticipation of appropriate medical care for the newborn, or it provides the family the opportunity to decide whether to continue the pregnancy. The authors described four cases of KTS diagnosed prenatally at different gestational ages. Prenatal diagnosis was based on sonographic detection of superficial multiple cystic structures spreading over the limb and body, with hemi-hypertrophy of the affected limb. Color Doppler ultrasound was employed to examine the presence and intensity of blood flow signals within the lesions and/or the presence of arteriovenous fistulae (AVF). A thorough examination was conducted to show the distribution of the masses, the presence of vascular anomalies inside the affected limb, or cystic lesions of internal organs. Particular attention was paid to the assessment of the skeletal system, including equal length of the long bones in the arms and legs, presence of hand/foot defects, or spine/rib anomalies. All patients were counseled by a multidisciplinary team that included a US specialist, geneticist, pediatric surgeon, and obstetrician. The prognosis for the fetus was determined based on gestational age at the time of diagnosis, the extent of the lesions, internal organ involvement, degree of vascularization, and the progression rate of hemangiomas.
Pang and Gao (2021) noted that KTS is a rare congenital disorder. A detailed prenatal ultrasound examination plays an important role in the diagnosis of KTS and the subsequent counseling and follow-up of the patient. These investigators presented the case of a 25-year-old woman who attended their department for a regular examination. At 18 weeks of gestation, the whole of the right lower extremity and right buttock were observed to be markedly thicker compared to the left one; however, the lengths of the right femur, tibia, and fibula were within the normal range. No marked edema or fluid/cystic spaces were detected in the lower limbs, and there were no other organ abnormalities. The vasculature in the right limb was visibly dilated, with significantly higher blood flow signals. No congenital embryonic veins were visible in either limb. Two weeks later, the right lower limb exhibited much more hypertrophy compared to the left limb. Amniocentesis and genetic tests showed normal results with a karyotype of 46 XX. Despite the normal karyotype, the family opted to terminate the pregnancy. The post-mortem examination confirmed asymmetric hypertrophy of the right limb in the fetus and showed a large area of marked dark-purple superficial capillary malformations occupying the skin of the right lower extremity. The enlargement of veins and soft tissue hypertrophy were also observed on post-natal X-ray and MRI. Autopsy revealed severe congestion in the right lower limb, leading to a final diagnosis of KTS. The authors concluded that KTS may be diagnosed prenatally based on the typical features observed during ultrasound examination.
Harnarayan and Harnanan (2022) stated that KTS is an unusual syndrome characterized by vascular and dermatologic manifestations, where patients demonstrate hemi-hypertrophy of the soft tissue and bones of one limb, cutaneous hemangiomas, and varicosities in anatomically abnormal positions. Described in 1900 by two French physicians, the etiology remained unclear until recently, when evidence emerged suggesting a genetic basis for this sporadic disorder. Genes encoding pathological angiogenic factors that cause vascular dysmorphogenesis have been identified, explaining the molecular basis of this syndrome. Several angiogenic genes have been identified; however, one gene, the AGGF1 (formerly VG5Q) gene, has been implicated in mutations involving patients diagnosed with KTS. Additionally, this syndrome has overlapping clinical features linked with “overgrowth syndromes,” where genetic mutations along somatic lines have been identified. These mutations involve the PI3K enzyme, part of the phosphoinositide 3-kinase pathway, which is encoded by the PIK3CA gene. This enzyme mediates embryonic cellular growth in utero, and diseases involved in this pathway are classified as members of the PIK3CA-related overgrowth syndrome. The authors reviewed the current understanding of the molecular genetics of this unusual but clinically challenging disorder and its differentiation from similar diseases linked with the PIK3CA gene and related overgrowth syndromes. They emphasized that fetal ultrasound with a detailed anatomic examination for abnormalities due to genetic conditions is a medically necessary approach for managing this disorder.
Gica et al. (2023) noted that KTS is a very rare vascular malformation syndrome, also referred to as a capillary-lymphatic-venous malformation with an unknown etiology. These investigators highlighted an interesting case of fetal KTS diagnosed prenatally in their department and confirmed postnatally, with a favorable evolution during the gestation and neonatal periods. This case was diagnosed at 26 weeks of gestation and characterized via ultrasound by the presence of superficial multiple cystic structures of different sizes spreading over the left leg, with hemi-hypertrophy and reduced mobility. The cystic lesions extended to the left buttock and pelvic area. The right leg and upper limbs appeared normal with good mobility. There were no signs of hyperdynamic circulation or fetal anemia; however, mild polyhydramnios was present. The ultrasound findings were confirmed postnatally, showing multiple cystic lesions and port wine stains on the left leg, along with hypertrophy and a fixed position. The lesions began to decrease in size, and the mobility of the leg improved by six months of life.
StatPearls’ webpage on “Klippel-Trenaunay-Weber syndrome” (Naganathan and Tadi, 2023) stated that KTS is a clinical diagnosis characterized by the presence of two of the three classic features. Imaging is recommended to examine the underlying venous/lymphatic malformations and soft tissue/bone hypertrophy, mapping the extent of disease and complications. Color Doppler ultrasound can serve as an initial step to evaluate varicosities, venous malformations, or the presence of thrombus formation. However, MRI and magnetic resonance venography (MRV) can be more useful in examining the extent of all underlying malformations.
Suspected Placenta Previa
Jenabi et al. (2023) noted that congenital abnormalities, as one of the fetal complications of placenta previa, may lead to health problems or disabilities for the child throughout life. In a systematic review and network meta-analysis, these researchers examined the relationship between placenta previa and congenital abnormalities. They retrieved potential studies from three electronic databases (PubMed/Medline, Scopus, and Web of Sciences) up to May 21, 2023, without limitations on time or language. A random effects model was applied for the meta-analysis, and heterogeneity was calculated using the I² statistic and Cochrane Q-test. All analyses were conducted at a significance level of 0.05 using STATA software, version 14. The quality assessment of the included studies was performed using the improved Newcastle-Ottawa Scale. In the initial search, 829 articles were retrieved, and ultimately, eight studies met the inclusion criteria for analysis in the meta-analysis. A significant association was reported between placenta previa and the risk of congenital abnormalities, with odds ratios (OR) of 1.81 (95% CI: 1.34 to 2.28) for crude forms and 6.38 (95% CI: 1.47 to 11.30) for adjusted studies. High heterogeneity was observed among the studies, with I² values of 97.9% (p = 0.000) for adjusted forms and 80.6% (p = 0.000) for crude forms; however, publication bias was not detected among the studies, and seven of the included studies were of high quality. The authors concluded that their findings provided evidence of a positive and significant association between placenta previa and congenital malformations, including all structural anomalies, chromosomal defects, and congenital hypothyroidism. They emphasized the necessity of monitoring for congenital abnormalities in the fetuses of mothers with placenta previa.
The authors also noted that several diagnostic methods for placenta previa were mentioned in the included studies. Four studies used only ultrasound (US) for diagnosis, while two studies diagnosed placenta previa using both US and during delivery (Crane et al., 1999; Sheiner et al., 2001). In the study by Brenner et al. (1978), placenta previa was diagnosed using the I-131-albumin radioisotope technique. The study by Salihu et al. (2003) also considered placenta previa. These included studies primarily addressed the use of conventional US rather than detailed ultrasound.
Furthermore, an UpToDate review on “Placenta previa: Management” (Lockwood and Russo-Stieglitz, 2024) does not mention detailed ultrasound as a management tool.
Doppler Ultrasound During Pregnancy
The American College of Radiology (Robbins et al., 2020; Bennett et al., 2011) states that transvaginal ultrasound (TVUS) is the initial imaging modality of choice for abnormal uterine or vaginal bleeding. Doppler techniques are reserved for specific scenarios where further characterization of a focal abnormality is needed, such as distinguishing between benign and malignant endometrial lesions or evaluating suspected vascular abnormalities. However, in the context of early pregnancy, Doppler analysis of uterine artery blood flow has not demonstrated clinical utility in managing first-trimester bleeding, as there is no significant difference in Doppler indices between normal and abnormal pregnancies complicated by bleeding (Pellizzari et al., 2020).
For placenta accreta spectrum (PAS), the primary diagnostic modality is obstetric ultrasonography, with color Doppler imaging providing critical adjunctive information. The American College of Obstetricians and Gynecologists, the Society of Gynecologic Oncology, and the Society for Maternal-Fetal Medicine (Cahill et al., 2018; ACOG, 2018) recommend using color Doppler to identify key features of PAS, including turbulent lacunar blood flow, increased subplacental vascularity, gaps in myometrial blood flow, and vessels bridging the placenta to the uterine margin.
The medical literature indicates that while Doppler techniques are valuable for assessing placental and uteroplacental circulation in various pregnancy complications, their utility in the acute diagnosis or management of placental abruption is minimal. Specifically, Doppler may demonstrate hemodynamic changes in select cases, but these findings are not sufficiently sensitive or specific to be relied upon for diagnosis or routine evaluation of abruption (Hernandez-Andrade et al., 2022; Schneider & Kinzler, 2025; Oyelese et al., 2025). The diagnosis of abruptio placenta remains primarily clinical, supported by grayscale ultrasound to identify retroplacental hematoma or other hemorrhagic lesions, but even ultrasound itself has limited sensitivity for abruption, especially in acute settings.
The main utility of Doppler in ectopic pregnancy is as an adjunct when grayscale findings are equivocal, but it is not part of standard clinical algorithms (Brennan et al., 1995; Hendricks et al., 2020).
Color and power Doppler are valuable adjuncts for characterizing local vascularity and guiding management in cornual (interstitial) or cesarean section scar ectopic pregnancy. For cornual ectopic pregnancy, transvaginal color Doppler can demonstrate increased peritrophoblastic vascularity, which may help confirm the diagnosis and monitor response to medical therapy, especially when methotrexate is used; this is particularly relevant given the high risk of hemorrhage with surgical intervention in this location. For cesarean scar ectopic pregnancy, color Doppler is routinely used to assess abnormal implantation, delineate the relationship of the gestational sac to the scar, and evaluate vascularity, which is critical for risk stratification and procedural planning (Bernardini et al., 1998; Liu et al., 2018). The Society for Maternal-Fetal Medicine specifically recommends ultrasound, including Doppler, as the primary imaging modality for the diagnosis and management of cesarean scar ectopic pregnancy (Miller et al., 2022).
For placental chorioangioma, diagnosis and surveillance rely on grayscale ultrasound and color Doppler to assess the vascularity of the tumor and its feeding vessels, which is critical for risk stratification and guiding intervention. Color Doppler is essential for identifying the hypervascular nature of chorioangiomas and monitoring changes in intratumoral blood flow, which may correlate with clinical outcomes and response to therapy (Zalel et al., 2002; Polat et al., 2002; Fan & Skupski, 2014).
Color Doppler ultrasound is not established as a diagnostic or management tool for circumvallate placenta. Current literature emphasizes that while Doppler ultrasound is essential for assessing placental function and vascular complications (e.g., preeclampsia, fetal growth restriction, placenta accreta), it is not indicated for the diagnosis or management of circumvallate placenta, as this condition is a morphological abnormality rather than a vascular one (Hernandez-Andrade et al., 2022; Abramowicz & Sheiner, 2008; Kennedy & Woodward, 2019; Meler et al., 2021; Turan et al., 2025).
The diagnosis and assessment of placental hemangioma, like other placental tumors, rely primarily on grayscale and color Doppler imaging to characterize the lesion’s vascularity and feeding vessels. Color Doppler is valuable for identifying the hypervascular nature of these tumors and for distinguishing them from other placental masses (Hernandez-Andrade et al., 2022).
There is evidence supporting the use of color Doppler ultrasound for the diagnosis or management of succenturiate placenta (accessory placental lobe). Succenturiate lobes are typically identified by grayscale and color Doppler ultrasound through visualization of separate placental lobes connected by vessels. Doppler evaluation focuses on intraplacental and fetal-placental circulation (Abramowicz & Sheiner, 2008; Hernandez-Andrade et al., 2022).
The assessment of umbilical cord coiling is performed by direct visualization and measurement of the antenatal umbilical coiling index, and the hemodynamic consequences are best evaluated with umbilical artery and vein Doppler (Predanic et al., 2006).
Marginal cord insertion is primarily diagnosed by grayscale and color Doppler ultrasound, which improve visualization of the placental cord insertion site and are recommended for this purpose (Rodriguez & Elinor, 2019; Tsakiridis et al., 2022).
The diagnosis and assessment of umbilical cord cysts rely on detailed grayscale and color Doppler imaging of the cord to characterize the cyst and to screen for associated fetal anomalies or aneuploidy, particularly when cysts are detected in the second or third trimester or are accompanied by other sonographic abnormalities (Moshiri et al., 2014; Krzyzanowsk et al., 2019; Zangen et al., 2010).
The diagnosis of velamentous cord insertion is best achieved by direct visualization with grayscale and color Doppler ultrasound, which significantly increases detection rates and should be routinely used for this purpose (Rodriguez & Elinor, 2019; Tsakiridis et al., 2022).
Adu-Bredu et al. (2023) present a practical, three-step guide for ultrasound screening of placenta accreta spectrum (PAS) tailored for clinicians and sonographers in resource-limited settings. The article emphasizes initial risk stratification based on clinical history (e.g., prior cesarean, placenta previa), followed by a focused ultrasound protocol that can be performed with or without Doppler capability. The guide details key grayscale ultrasound features suggestive of PAS, such as loss of the clear zone, placental lacunae, myometrial thinning, and abnormal uterine-bladder interface. When Doppler is available, the presence of turbulent flow within placental lacunae and increased subplacental vascularity are highlighted as important adjuncts to improve diagnostic confidence. The approach is designed to be accessible for providers with limited experience, aiming to increase antenatal detection rates and facilitate timely referral and multidisciplinary management, thereby reducing maternal morbidity and mortality in low-resource environments.
Ultrasound and Threatened Miscarriage During First Trimester
The 2023 update of the ACR Appropriateness Criteria® for Acute Pelvic Pain in the Reproductive Age Group emphasizes that transvaginal and transabdominal ultrasound are the first-line imaging modalities for evaluating threatened miscarriage and first-trimester vaginal bleeding. These modalities are considered complementary, as each provides unique and essential clinical information for effective patient management. The rationale for this recommendation is that ultrasound is highly sensitive for detecting intrauterine pregnancy, assessing fetal viability, and identifying potential complications such as ectopic pregnancy or retained products of conception, all while avoiding ionizing radiation exposure to the fetus. The guideline emphasizes that the choice of imaging should be guided by clinical suspicion, β-hCG status, and the need to minimize fetal risk, with ultrasound being the preferred first-line modality in the acute setting for reproductive-age patients presenting with pelvic pain and/or bleeding in early pregnancy. In cases of first-trimester vaginal bleeding, the guidelines also consider duplex Doppler ultrasound of the pregnant uterus or adnexa as "may be appropriate", particularly when additional vascular information is needed to evaluate conditions like ectopic pregnancy or gestational trophoblastic disease. However, color Doppler and duplex Doppler are not universally required and are used selectively based on clinical suspicion and initial grayscale ultrasound findings.
According to the 2018 American College of Obstetricians and Gynecologists (ACOG) guidelines, transvaginal ultrasonography is the preferred imaging modality for threatened miscarriage and first-trimester vaginal bleeding. Color Doppler or duplex Doppler is not routinely recommended by ACOG for the evaluation of threatened miscarriage or first-trimester bleeding. Their use is generally reserved for specific clinical scenarios where vascular assessment is necessary (e.g., suspected gestational trophoblastic disease or abnormal placentation), but not for routine evaluation of early pregnancy loss.
Glossary of Terms
| Term | Definition |
|---|---|
| 3D and 4D ultrasound | 3D: Provides three-dimensional static images. 4D: Adds real-time motion to 3D imaging (commonly used in obstetrics for fetal imaging). |
| B-mode (brightness mode) / grayscale ultrasound | Most common and basic form of ultrasound. Produces two-dimensional (2D) images of internal structures. Used for general anatomical assessment (e.g., fetal development, organ structure). |
| Color Doppler ultrasound | An enhanced form of Doppler ultrasound. Uses color to represent the presence, direction and relative velocity of blood flow within vessels or organs. Color-coded overlay on grayscale image (e.g., red for flow toward the probe, blue for away). Does not quantify flow. Useful in evaluating vascularity in organs or masses. Used for evaluating fetal heart, umbilical cord, uterine arteries, or abnormal vascularity (e.g., in ectopic pregnancy or tumors). |
| Detailed ultrasound (grayscale or B-mode) | Provides high-resolution anatomical images. Evaluates fetal development, uterine and adnexal structures, and detects abnormalities. Black-and-white, two-dimensional (2D) images. Does not show or quantify blood flow. Used in obstetric scans, early pregnancy assessments, and structural evaluations. |
| Doppler ultrasound | Non-invasive test that can depict blood flow by bouncing high-frequency sound waves off of red blood cells to create images of blood vessels, tissues, and organs. |
| Duplex Doppler ultrasound | Combines B-mode (grayscale) imaging with spectral (pulsed-wave) Doppler. Often includes color flow Doppler imaging. Provides both anatomical detail and quantitative blood flow data (e.g., velocity, flow waveform). Real-time image with a graph showing flow velocity over time. Assesses uterine or ovarian blood flow, fetal circulation, or vascular pathologies. |
| Spectral Doppler ultrasound | Provides quantitative analysis of blood flow velocities |
Appendix
According to the Society for Maternal Fetal Medicine (SMFM, 2012), a detailed fetal anatomic ultrasound (CPT code 76811) includes all of the components of the routine fetal ultrasound (CPT code 76805), plus a detailed fetal anatomical survey. The SMFM (2012) has stated that the following are fetal and maternal anatomical components for the detailed fetal anatomic ultrasound (CPT code 76811). Not all components will be required. Components considered integral to the code are marked with an asterisk: Footnote2*Component considered integral to the CPT code 76811.
Evaluation of Intracranial, Facial, and Spinal Anatomy
- Lateral ventriclesFootnote2*, third and fourth ventricles
- CerebellumFootnote2*, integrity of lobesFootnote2*, vermisFootnote2*
- Cavum septum pellucidum
- Cisterna magna measurementFootnote2*
- Nuchal thickness measurement (15-20 weeks)Footnote2*
- Integrity of cranial vault
- Examination of brain parenchyma, (e.g. for calcifications)
- Ear position, size
- Face
- Upper lip integrityFootnote2*
- PalateFootnote2*
- Facial profileFootnote2*
- Evaluation of the neck (e.g. for masses)
Evaluation of the Chest
- Presence of massesFootnote2*
- Pleural effusionFootnote2*
- Integrity of both sides of the diaphragmFootnote2*
- Appearance of ribs
Evaluation of the Heart
- Cardiac location and axisFootnote2*
- Outflow tractsFootnote2*
Evaluation of the Abdomen
- BowelFootnote2*
- Adrenal glands
- Gallbladder
- Liver
- Spleen
- AscitesFootnote2*
- Masses
Evaluation of Genitalia
- Gender (whether or not parents wish to know sex of child)
Evaluation of Limbs
- Number, size, and architectureFootnote2*
- Anatomy and position of handsFootnote2*
- Anatomy and position of feetFootnote2*
Evaluation of the Placenta and Cord
- Placental cord insertion siteFootnote2*
- Placental massesFootnote2*
- Umbilical-cord (number of arteries)
Evaluation of Amniotic Fluid
- Amniotic Fluid IndexFootnote2*
- Evaluation of the cervix (Not required)
- Evaluation of the maternal adnexa when feasibleFootnote2*
Note: If any of the required fetal or maternal components are non-visualized due to fetal position, late gestational age, maternal habitus, etc., it must be clearly noted in the ultrasound report in order to meet the requirements to bill for the service (SMFM, 2012).
Follow-up ultrasound performed after a detailed anatomic ultrasound (CPT code 76811), should be reported as CPT 76816 (Ultrasound, pregnant uterus, real time with image documentation, follow-up) (SMFM, 2012). This includes performing a focused assessment of fetal size by measuring the BPD, abdominal circumference, femur length, or other appropriate measurements, or a detailed re-examination of a specific organ or system known or suspected to be abnormal.
CPT code 76805 (Ultrasound, pregnant uterus, real time with image documentation, fetal and maternal evaluation, after first trimester (greater than or equal to 14 weeks 0 days), would be reported to determine the number of fetuses, amniotic/chorionic sacs, survey of intracranial, spinal, and abdominal anatomy, evaluation of a 4-chamber heart view, assessment of the umbilical cord insertion site, assessment of amniotic fluid volume, and evaluation of maternal adnexa when visible when appropriate (SMFM, 2012).
CPT code 76805 and ICD-10 code Z36 are reported when performing a routine screening ultrasound (no maternal or fetal indications or abnormal findings) (SMFM, 2012).
References
The above policy is based on the following references:
- Abramowicz JS, Sheiner E. Ultrasound of the placenta: A systematic approach. Part II: Functional assessment (Doppler). Placenta. 2008;29(11):921-929.
- ACOG Committee on Practice Bulletins -- Obstetrics. ACOG Practice Bulletin: Clinical management guidelines for obstetrician-gynecologists number 92, April 2008 (replaces practice bulletin number 87, November 2007). Use of psychiatric medications during pregnancy and lactation. Obstet Gynecol. 2008;111(4):1001-1020.
- ACOG Committee on Practice Bulletins. ACOG Practice Bulletin No. 77: Screening for fetal chromosomal abnormalities. Obstet Gynecol. 2007;109(1):217-227.
- Adu-Bredu TK, Rijken MJ, Nieto-Calvache AJ, et al. A simple guide to ultrasound screening for placenta accreta spectrum for improving detection and optimizing management in resource limited settings. Int J Gynaecol Obstet. 2023;160(3):732-741.
- Ahmed BI. The new 3D/4D based spatio-temporal imaging correlation (STIC) in fetal echocardiography: A promising tool for the future. J Matern Fetal Neonatal Med. 2014;27(11):1163-1168.
- Alfirevic Z, Stampalija T, Dowswell T. Fetal and umbilical Doppler ultrasound in high-risk pregnancies. Cochrane Database Syst Rev. 2017;6:CD007529.
- Alfirevic Z, Stampalija T, Gyte GM. Fetal and umbilical Doppler ultrasound in normal pregnancy. Cochrane Database Syst Rev. 2010;(8):CD001450.
- Alfirevic Z, Stampalija T, Gyte GM. Fetal and umbilical Doppler ultrasound in high-risk pregnancies. Cochrane Database Syst Rev. 2010;(1):CD007529.
- Alfirevic Z, Stampalija T, Medley N. Fetal and umbilical Doppler ultrasound in normal pregnancy. Cochrane Database Syst Rev. 2015;4:CD001450.
- American Academy of Pediatrics (AAP) and American College of Obstetricians and Gynecologists (ACOG). Guidelines for Perinatal Care. 4th ed. Elk Grove Village, IL: AAP; August 1997.
- American College of Obstetricians and Gynecologists (ACOG). Placenta accreta spectrum. Obstetric Care Consensus No. 7. Obstet Gynecol. 2018;132:e259-e275.
- American College of Obstetricians and Gynecologists (ACOG) Committee on Ethics. ACOG Committee Opinion. Number 297, August 2004. Nonmedical use of obstetric ultrasonography. Obstet Gynecol. 2004;104(2):423-424.
- American College of Obstetricians and Gynecologists (ACOG) Committee on Health Care for Underdeserved Women; ACOG Committee on Obstetric Practice. ACOG committee opinion. Number 316, October 2005. Smoking cessation during pregnancy. Obstet Gynecol. 2005;106(4):883-888.
- American College of Obstetricians and Gynecologists (ACOG), Committee on Obstetric Practice. Guidelines for diagnostic imaging during pregnancy. ACOG Committee Opinion No. 158. Washington, DC: ACOG; September 1995.
- American College of Obstetricians and Gynecologists (ACOG), Committee on Practice Bulletins -- Obstetrics. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists. Prenatal diagnosis of fetal chromosomal abnormalities. Obstet Gynecol. 2001;97(5 Pt 1):suppl 1-12.
- American College of Obstetricians and Gynecologists (ACOG), Committee on Practice Bulletins -- Obstetrics. Ultrasonography in pregnancy. ACOG Practice Bulletin No. 58. Washington, DC: ACOG; December 2004.
- American College of Obstetricians and Gynecologists (ACOG), Committee on Practice Bulletins -- Obstetrics. Ultrasonography in pregnancy. ACOG Practice Bulletin No. 98. Washington, DC: ACOG; October 2008.
- American College of Obstetricians and Gynecologists (ACOG), Committee on Practice Bulletins -- Obstetrics. Ultrasonography in pregnancy. ACOG Practice Bulletin No. 101. Washington, DC: ACOG; February 2009.
- American College of Obstetricians and Gynecologists (ACOG). Multiple gestation. ACOG Technical Bulletin No.131. Washington, DC: ACOG; August 1989.
- American College of Obstetricians and Gynecologists. ACOG Committee Opinion #296: First-trimester screening for fetal aneuploidy. Obstet Gynecol. 2004;104(1):215-217.
- American College of Obstetricians and Gynecologists' Committee on Practice Bulletins -- Gynecology. ACOG Practice Bulletin No. 200: Early pregnancy loss. Obstet Gynecol. 2018;132(5):e197-e207.
- Antsaklis A, Daskalakis G, Theodora M, et al. Assessment of nuchal translucency thickness and the fetal anatomy in the first trimester of pregnancy by two- and three-dimensional ultrasonography: A pilot study. J Perinat Med. 2011;39(2):185-193.
- Bansal R, Goyal MK, Modi M. Management of myasthenia gravis during pregnancy. Indian J Pharmacol. 2018;50(6):302-308.
- Barnett SB, Maulik D; International Perinatal Doppler Society. Guidelines and recommendations for safe use of Doppler ultrasound in perinatal applications. J Matern Fetal Med. 2001;10(2):75-84.
- Bellussi F, Ghi T, Youssef A, et al. The use of intrapartum ultrasound to diagnose malpositions and cephalic malpresentations. Am J Obstet Gynecol. 2017;217(6):633-641.
- Benacerraf BR, Shipp TD, Bromley B. Improving the efficiency of gynecologic sonography with 3-dimensional volumes: A pilot study. J Ultrasound Med. 2006;25(2):165-171.
- Benacerraf BR, Shipp TD, Bromley B. Three-dimensional US of the fetus: Volume imaging. Radiology. 2006;238(3):988-996.
- Benacerraf BR, Shipp TD, Bromley B. How sonographic tomography will change the face of obstetric sonography: A pilot study. J Ultrasound Med. 2005;24(3):371-378.
- Benacerraf CR. Sonographic findings associated with fetal aneuploidy. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed February 2015.
- Bennett GL, Andreotti RF, Lee SI, et al. ACR appropriateness criteria(®) on abnormal vaginal bleeding. J Am Coll Radiol. 2011;8(7):460-468.
- Bernardini L, Valenzano M, Foglia G. Spontaneous interstitial pregnancy on a tubal stump after unilateral adenectomy followed by transvaginal colour Doppler ultrasound. Hum Reprod. 1998;13(6):1723-1726.
- Bird SJ, Stafford IP, Dildy GA, III. Management of myasthenia gravis in pregnancy. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
- Bofill JA, Sharp GH. Obstetric sonography. Who to scan, when to scan, and by whom. Obstet Gynecol Clin North Am. 1998;25(3):465-478.
- Bohilțea RE, Dima V, Ducu I, et al. Clinically relevant prenatal ultrasound diagnosis of umbilical cord pathology. Diagnostics (Basel). 2022;12(2):236.
- Brennan DF. Ectopic pregnancy--Part II: Diagnostic procedures and imaging. Acad Emerg Med. 1995;2(12):1090-1097.
- Brenner WE, Edelman DA, Hendricks CH. Characteristics of patients with placenta previa and results of expectant management. Am J Obstet Gynecol. 1978;132(2):180-191.
- Bricker L, Garcia J, Henderson J, et al. Ultrasound screening in pregnancy: A systematic review of the clinical effectiveness, cost-effectiveness and women's views. Health Technol Assess. 2000;4(16):i-vi, 1-193.
- Bricker L, Medley N, Pratt JJ. Routine ultrasound in late pregnancy (after 24 weeks' gestation). Cochrane Database Syst Rev. 2015;6:CD001451.
- Brogly SB, Abzug MJ, Watts DH, et al. Birth defects among children born to HIV-infected women: Pediatric AIDS Clinical Trials Protocols 219 and 219C. Pediatr Infect Dis J. 2010;29(8):721-727.
- Buchanan-Hughes A, Bobrowska A, Visintin C, et al. Velamentous cord insertion: Results from a rapid review of incidence, risk factors, adverse outcomes and screening. Syst Rev. 2020;9(1):147.
- Buonsenso D, Raffaelli F, Tamburrini E, et al. Clinical role of lung ultrasound for diagnosis and monitoring of COVID-19 pneumonia in pregnant women. Ultrasound Obstet Gynecol. 2020;56(1):106-109.
- Castro AA, Lima FJC, Sousa-Rodrigues CF, Barbosa FT. Accuracy of ultrasound to detect thrombosis in pregnancy: A systematic review. Rev Assoc Med Bras (1992). 2017;63(3):278-283.
- Centers for Disease Control and Prevention (CDC). Sexually Transmitted Infections Treatment Guidelines, 2021. Atlanta, GA: CDC; 2021.
- Chen M, Lee CP, Lam YH, et al. Comparison of nuchal and detailed morphology ultrasound examinations in early pregnancy for fetal structural abnormality screening: A randomized controlled trial. Ultrasound Obstet Gynecol. 2008;31(2):136-146; discussion 146.
- Chen M, Wang HF, Leung TY, et al. First trimester measurements of nasal bone length using three-dimensional ultrasound. Prenat Diagn. 2009;29(8):766-770.
- Clinical Practice Obstetrics Committee; Maternal Fetal Medicine Committee, Delaney M, Roggensack A, Leduc DC, et al. Guidelines for the management of pregnancy at 41+0 to 42+0 weeks. J Obstet Gynaecol Can. 2008;30(9):800-823.
- Committee on Obstetric Practice. Committee Opinion No. 723: Guidelines for diagnostic imaging during pregnancy and lactation [published correction appears in Obstet Gynecol. 2018 Sep;132(3):786.
- Crane J, Scott H, Stewart A, et al. Transvaginal ultrasonography to predict preterm birth in women with bicornuate or didelphus uterus. J Matern Fetal Neonatal Med. 2012;25(10):1960-1964.
- Crane JMG, van den Hof MC, Dodds L, et al. Neonatal outcomes with placenta previa. Obstet Gynecol. 1999;93(4):541-544.
- Czeizel AE, Puhó EH, Dakhlaoiu A, et al. Association between uterus uni/bicornis in pregnant women and postural deformities in their offspring. Am J Obstet Gynecol. 2011;205(6):560.e1-6.
- Davies G, Wilson RD, Desilets V, et al. Amniocentesis and women with hepatitis B, hepatitis C, or human immunodeficiency virus. J Obstet Gynaecol Can. 2003;25(2):145-148, 149-152.
- Demianczuk NN, Van Den Hof MC, Farquharson D, et al. The use of first trimester ultrasound. Obstet Gynaecol Can. 2003;25(10):864-875.
- Doyle T, Kavanaugh-McHugh A. Tetralogy of Fallot (TOF): Management and outcome. UpToDate [online serial], Waltham, MA: UpToDate; reviewed December 2024.
- Dubbins PA. Screening for chromosomal abnormality. Semin Ultrasound CT MR. 1998;19(4):310-317.
- Evans MI, Chervenak FA, Eden RD. Report of the Council on Scientific Affairs of the American Medical Association: Ultrasound evaluation of the fetus. Fetal Diagnosis Therapy. 1991;6(3-4):132-147.
- Expert Panel on GYN and OB Imaging, Brook OR, Dadour JR, et al. ACR Appropriateness Criteria® Acute Pelvic Pain in the Reproductive Age Group: 2023 Update. J Am Coll Radiol. 2024;21(6S):S3-S20.
- Expert Panel on GYN and OB Imaging, Robbins JB, Sadowski EA, et al. ACR Appropriateness Criteria® Abnormal Uterine Bleeding. J Am Coll Radiol. 2020;17(11S):S336-S345.
- Fan M, Skupski DW. Placental chorioangioma: Literature review. J Perinat Med. 2014;42(3):273-279.
- Fuchs KM, Society for Maternal-Fetal Medicine (SMFM). Isolated fetal choroid plexus cysts. Their implications and outcome. Contemp Obstet Gynecol. April 1, 2013.
- Garmel SH, D'Alton ME. Diagnostic ultrasound in pregnancy: An overview. Semin Perinatol. 1994;18(3):117-132.
- Gaspari L, Paris F, Nicolino M, et al. Fetal ovarian cysts: An early manifestation of McCune-Albright syndrome? Prenat Diagn. 2012;32(9):859-63.
- Gebauer C, Lowe N. The biophysical profile: Antepartal assessment of fetal well-being. J Obstet Gynecol Neonatal Nursing. 1993;22(2):115-123.
- Ghi T, De Musso F, Maroni E, et al. The pregnancy outcome in women with incidental diagnosis of septate uterus at first trimester scan. Hum Reprod. 2012;27(9):2671-2675.
- Gica N, Dumitru A, Panaitescu AM, et al. Prenatal ultrasound diagnosis of Klippel-Trenaunay syndrome. Diagnostics (Basel). 2023;13(22):3400.
- Gimovsky ML, Tejero Rosa E, Sepulveda W. Single umbilical artery. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2018.
- Gindes L, Weissmann-Brenner A, Zajicek M, et al. Three-dimensional ultrasound demonstration of the fetal palate in high-risk patients: The accuracy of prenatal visualization. Prenat Diagn. 2013;33(5):436-441.
- Gomez KJ, Copel JA. Ultrasound screening for fetal structural anomalies. Curr Opin Obstet Gynecol. 1993;5(2):204-210.
- Goncalves LF, Lee W, Espinoza J, Romero R. Three- and 4-dimensional ultrasound in obstetric practice: Does it help? J Ultrasound Med. 2005;24(12):1599-1624.
- Grivell RM, Wong L, Bhatia V. Regimens of fetal surveillance for impaired fetal growth. Cochrane Database Syst Rev. 2012;6:CD007113.
- Harnarayan P, Harnanan D. The Klippel-Trenaunay syndrome in 2022: Unravelling its genetic and molecular profile and its link to the limb overgrowth syndromes. Vasc Health Risk Manag. 2022;18:201-209.
- Hata T, Kanenishi K, Inubashiri E, et al. Three-dimensional sonographic features of placental abnormalities. Gynecol Obstet Invest. 2004;57(2):61-65.
- Hata T, Tanaka H, Noguchi J. 3D/4D sonographic evaluation of amniotic band syndrome in early pregnancy: A supplement to 2D ultrasound. J Obstet Gynaecol Res. 2011;37(6):656-660.
- Harnarayan P, Harnanan D. The Klippel-Trenaunay syndrome in 2022: Unravelling its genetic and molecular profile and its link to the limb overgrowth syndromes. Vasc Health Risk Manag. 2022;18:201-209.
- Harrington J, Palmert MR. Definition, etiology, and evaluation of precocious puberty. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2022.
- Hayes DJL, Warland J, Parast MM, et al. Umbilical cord characteristics and their association with adverse pregnancy outcomes: A systematic review and meta-analysis. PLoS One. 2020;15(9):e0239630.
- Heazell AE, Hayes DJ, Whitworth M, et al. Biochemical tests of placental function versus ultrasound assessment of fetal size for stillbirth and small-for-gestational-age infants. Cochrane Database Syst Rev. 2019;5:CD012245
- Heinonen PK. Limb anomalies among offspring of women with a septate uterus: A report of three cases. Early Hum Dev. 1999;56(2-3):179-184.
- Hendriks E, Rosenberg R, Prine L. Ectopic pregnancy: Diagnosis and management. Am Fam Physician. 2020;101(10):599-606.
- Henrichs J, Verfaille V, Jellema P, et al. Effectiveness of routine third trimester ultrasonography to reduce adverse perinatal outcomes in low risk pregnancy (the IRIS study): Nationwide, pragmatic, multicentre, stepped wedge cluster randomised trial. BMJ. 2019;367:l5517.
- Hernandez-Andrade E, Huntley ES, Bartal MF, et al. Doppler evaluation of normal and abnormal placenta. Ultrasound Obstet Gynecol. 2022;60(1):28-41.
- Hughes KM, Kane SC, Haines TP, Sheehan PM. Cervical length surveillance for predicting spontaneous preterm birth in women with uterine anomalies: A cohort study. Acta Obstet Gynecol Scand. 2020;99(11):1519-1526.
- Institute for Clinical Systems Improvement (ICSI). Prenatal ultrasound as a screening test. ICSI Technology Assessment Report No. 16. Bloomington, MN: ICSI; updated October 2002.
- Ivanitskaya O, Andreeva E, Odegova N. Prenatal diagnosis of Klippel-Trenaunay syndrome: Series of four cases and review of the literature. Ultrasound. 2020;28(2):91-102.
- Jauniaux E, Ayres-de-Campos D; FIGO Placenta Accreta Diagnosis and Management Expert Consensus Panel. FIGO consensus guidelines on placenta accreta spectrum disorders: Introduction. Int J Gynaecol Obstet. 2018;140(3):261-264.
- Jenabi E, Bashirian S, Khoshravesh S. The association between of placenta previa and congenital abnormalities: A systematic review and network meta-analysis. BMC Pediatr. 2023;23(1):606.
- Jessop FA, Lees CC, Pathak S, et al. Umbilical cord coiling: Clinical outcomes in an unselected population and systematic review. Virchows Arch. 2014;464(1):105-112.
- Ji EK, Pretorius DH, Newton R, et al. Effects of ultrasound on maternal-fetal bonding: A comparison of two- and three-dimensional imaging. Ultrasound Obstet Gynecol. 2005;25(5):473-477.
- Jones NW, Raine-Fenning N, Mousa H, et al. Evaluation of the intraobserver and interobserver reliability of data acquisition for three-dimensional power Doppler angiography of the whole placenta at 12 weeks gestation. Ultrasound Med Biol. 2010;36(9):1405-1411.
- Junior EA, Santana EFM, Rolo LC, et al. Prenatal diagnosis of congenital syphilis using two- and three-dimensional ultrasonography: Case report. Case Rep Infect Dis. 2012;2012:478436.
- Jurkovic D. Three-dimensional ultrasound in gynecology: A critical evaluation. Ultrasound Obstet Gynecol. 2002;19(2):109-117.
- Kanenishi K, Hanaoka U, Noguchi J, et al. 4D ultrasound evaluation of fetal facial expressions during the latter stages of the second trimester. Int J Gynaecol Obstet. 2013;121(3):257-260.
- Kennedy AM, Woodward PJ. A radiologist's guide to the performance and interpretation of obstetric Doppler US. Radiographics. 2019;39(3):893-910.
- Krishnan R, Deal L, Chisholm C, et al. Concordance between obstetric anatomic ultrasound and fetal echocardiography in detecting congenital heart disease in high-risk pregnancies. J Ultrasound Med. 2021;40(10):2105-2112.
- Krzyzanowski A, Kwiatek M, Geca T, et al. Modern ultrasonography of the umbilical cord: Prenatal diagnosis of umbilical cord abnormalities and assessment of fetal wellbeing. Med Sci Monit. 2019;25:3170-3180.
- Kupesic S, Kurjak A. Diagnosis and treatment outcome of the septate uterus. Croat Med J. 1998;39(2):185-190.
- Kupesic S, Kurjak A, Hajder E. Ultrasonic assessment of the postmenopausal uterus. Maturitas. 2002;41(4):255-267.
- Kurjak A, Abo-Yaqoub S, Stanojevic M, et al. The potential of 4D sonography in the assessment of fetal neurobehavior -- multicentric study in high-risk pregnancies. J Perinat Med. 2010;38(1):77-82.
- Kurjak A, Kupesic S, Simunic V. Ultrasonic assessment of the peri- and postmenopausal ovary. Maturitas. 2002;41(4):245-254.
- Kurjak A, Miskovic B, Andonotopo W, et al. How useful is 3D and 4D ultrasound in perinatal medicine? J Perinat Med. 2007;35(1):10-27.
- Lakhani K, Seifalian AM, Atiomo WU, Hardiman P. Polycystic ovaries. Br J Radiol. 2002;75(889):9-16.
- Larcher L, Jauniaux E, Lenzi J, et al. Ultrasound diagnosis of placental and umbilical cord anomalies in singleton pregnancies resulting from in-vitro fertilization. Placenta. 2023;131:58-64.
- Laufer MR, DeCherney AH. Congenital uterine anomalies: Clinical manifestations and diagnosis. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed August 2018; December 2020; December 2021; December 2022.
- Liu D, Yang M, Wu Q. Application of ultrasonography in the diagnosis and treatment of cesarean scar pregnancy. Clin Chim Acta. 2018;486:291-297.
- Liu Q, Zhang Q, Liu P. The diagnostic accuracy of transabdominal and transvaginal color Doppler ultrasound for pregnant women with vasa previa and velamentous cord insertion. J Environ Public Health. 2022;2022:1685783.
- Lockwood CJ, Russo-Stieglitz K. Placenta previa: Management. UpToDate [online serial], Waltham, MA: UpToDate; reviewed December 2024.
- Malini S, Valdes C, Malinak LR. Sonographic diagnosis and classification of anomalies of the female genital tract. J Ultrasound Med. 1984;3(9):397-404.
- Martinez-Frías ML, Bermejo E, Rodríguez-Pinilla E, et al. Congenital anomalies in the offspring of mothers with a bicornuate uterus. Pediatrics. 1998;101(4):E10.
- McDonald-McGinn DM, Hain HS, Emanuel BS, Zackai EH. 22q11.2 Deletion syndrome. GeneReviews [internet]. Last updated: February 27, 2020. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1523/. Accessed July 22, 2022.
- Meler E, Martínez J, Boada D, Mazarico E, Figueras F. Doppler studies of placental function. Placenta. 2021;108:91-96.
- Messerlian GM, Farina A, Palomaki GE. First-trimester combined test and integrated tests for screening for Down syndrome and trisomy 18. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2021.
- Morin L, Van den Hof MC; Society of Obstetricians and Gynaecologists of Canada. SOGC clinical practice guidelines. Ultrasound evaluation of first trimester pregnancy complications. Number 161, June 2005. Int J Gynaecol Obstet. 2006;93(1):77-81.
- Moshiri M, Zaidi SF, Robinson TJ, et al. Comprehensive imaging review of abnormalities of the umbilical cord. Radiographics. 2014;34(1):179-196.
- Naganathan S, Tadi P. Klippel-Trenaunay-Weber syndrome. StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; updated: April 14, 2023. Available at: https://www.ncbi.nlm.nih.gov/books/NBK558989/. Accessed October 21, 2024.
- Negm SM, Kamel RA, El-Zayat HA, et al. The value of three-dimensional ultrasound in identifying Mullerian anomalies at risk of adverse pregnancy outcomes. J Matern Fetal Neonatal Med. 2022;35(16):3201-3208.
- No authors listed. AIUM practice parameter for the performance of detailed second- and third-trimester diagnostic obstetric ultrasound examinations. J Ultrasound Med. 2019;38(12):3093-3100.
- No authors listed. Committee Opinion No. 723 Summary: Guidelines for diagnostic imaging during pregnancy and lactation. Obstet Gynecol. 2017;130(4):933-934.
- Norwitz ER, Hicks CB. Syphilis in pregnancy. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
- Oyelese Y, Litman E, Hecht JL, Hernandez-Andrade E, Kinzler WL. Hemorrhagic placental lesions on ultrasound: A continuum of placental abruption. J Perinat Med. Published online May 5, 2025.
- Pang H-Q, Gao Q-Q. Prenatal ultrasonographic findings in Klippel-Trenaunay syndrome: A case report. World J Clin Cases. 2021;9(35):10994-10998.
- Pellizzari P, Pozzan C, Marchiori S, Zen T, Gangemi M. Assessment of uterine artery blood flow in normal first-trimester pregnancies and in those complicated by uterine bleeding. Ultrasound Obstet Gynecol. 2002;19(4):366-370.
- Pergialiotis V, Kotrogianni P, Koutaki D, et al. Umbilical cord coiling index for the prediction of adverse pregnancy outcomes: A meta-analysis and sequential analysis. J Matern Fetal Neonatal Med. 2020;33(23):4022-4029.
- Polat P, Suma S, Kantarcý M, Alper F, Levent A. Color Doppler US in the evaluation of uterine vascular abnormalities. Radiographics. 2002;22(1):47-53.
- Predanic M, Perni SC, Chervenak FA. Antenatal umbilical coiling index and Doppler flow characteristics. Ultrasound Obstet Gynecol. 2006;28(5):699-703.
- Rasmussen SA, Chu SY, Kim SY, et al. Maternal obesity and risk of neural tube defects: A metaanalysis. Am J Obstet Gynecol. 2008; 198:611–619.
- Richardson A, Gallos I, Dobson S, et al. Accuracy of first-trimester ultrasound in diagnosis of tubal ectopic pregnancy in the absence of an obvious extrauterine embryo: Systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2016;47(1):28-37.
- Ridout AE, Ibeto LA, Ross GN, et al. Cervical length and quantitative fetal fibronectin in the prediction of spontaneous preterm birth in asymptomatic women with congenital uterine anomaly. Am J Obstet Gynecol. 2019;221(4):341.e1-341.e9.
- Rodney WM, Deutchman ME, Hartman, KJ, et al. Obstetric ultrasound by family physicians. J Family Practice. 1992;34(2):186-200.
- Rodriguez D, Eliner Y. Performance of ultrasound for the visualization of the placental cord insertion. Curr Opin Obstet Gynecol. 2019;31(6):403-409.
- Salihu HM, Li Q, Rouse DJ, Alexander GR. Placenta previa: Neonatal death after live births in the United States. Am J Obstet Gynecol. 2003;188(5):1305-1309.
- Salvesen K. Routine ultrasound scanning in pregnancy. BMJ. 1993;307(6911):1064.
- Schneider E, Kinzler WL. Placental abruption: Pathophysiology, diagnosis, and management. Clin Obstet Gynecol. 2025;68(1):98-104.
- Seeds JW. The routine or screening obstetrical ultrasound examination. Clin Obstet Gynecol. 1996;39(4):814-830.
- Sharma R, Radhakrishnan G, Manchanda S, Singh S. Umbilical coiling index assessment during routine fetal anatomic survey: A screening tool for fetuses at risk. J Obstet Gynaecol India. 2018;68(5):369-375.
- Sharp GC, Stock SJ, Norman JE. Fetal assessment methods for improving neonatal and maternal outcomes in preterm prelabour rupture of membranes. Cochrane Database Syst Rev. 2014;10:CD010209.
- Sheiner E, Shoham-Vardi I, Hallak M, et al. Placenta previa: Obstetric risk factors and pregnancy outcome. J Maternal-Fetal Med. 2001;10(6):414-419.
- Shipp TD. Overview of ultrasound examination in obstetrics and gynecology. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed December 2021.
- Sinkin JA, Craig WY, Jones M, et al. Perinatal outcomes associated with isolated velamentous cord insertion in singleton and twin pregnancies. J Ultrasound Med. 2018;37(2):471-478.
- Society of Gynecologic Oncology; American College of Obstetricians and Gynecologists and the Society for Maternal–Fetal Medicine, Cahill AG, et al. Placenta accreta spectrum. Am J Obstet Gynecol. 2018;219(6):B2-B16.
- Society for Maternal-Fetal Medicine (SMFM), Miller R, Gyamfi-Bannerman C; Publications Committee. Society for Maternal-Fetal Medicine Consult Series #63: Cesarean scar ectopic pregnancy. Am J Obstet Gynecol. 2022;227(3):B9-B20.
- Society for Maternal Fetal Medicine (SMFM). Multi-society guideline for coding, billing, and clinician training for detailed fetal anatomy ultrasound in the first trimester. J Ultrasound Med. 2025;44(8):1519-1521.
- Society for Maternal-Fetal Medicine (SMFM). Single umbilical artery: What you need to know. Publications & Guidelines. Washington, DC: SMFM; February 1, 2013. Available at: https://www.smfm.org/publications/104-single-umbilical-artery-what-you-need-to-know. Accessed March 7, 2019.
- Society for Maternal Fetal Medicine (SMFM), Coding Committee. White paper on ultrasound code 76811. Announcements. Washington, DC: SMFM; revised May 26, 2012.
- Society for Maternal-Fetal Medicine (SMFM), Coding Committee. Coding for Zika virus. Washington, DC: SMFM; updated August 22, 2016.
- Society for Maternal-Fetal Medicine (SMFM), Coding Committee. White paper on ultrasound code 76811. Announcements. Washington, DC: SMFM; May 24, 2004.
- Stampalija T, Gyte GM, Alfirevic Z. Utero-placental Doppler ultrasound for improving pregnancy outcome. Cochrane Database Syst Rev. 2010;(9):CD008363.
- Stothard KJ, Tennant PW, Bell R, Rankin J. Maternal overweight and obesity and the risk of congenital anomalies: A systematic review and metaanalysis. JAMA. 2009; 301:636–650.
- Tao H, Wang R, Liu W, et al. The value of intrapartum ultrasound in the prediction of persistent occiput posterior position: Systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2019;238:25-32.
- Timor-Tritsch IE, Platt LD. Three-dimensional ultrasound experience in obstetrics. Curr Opin Obstet Gynecol. 2002;14(6):569-575.
- Tonni G, Grisolia G, Sepulveda W. Second trimester fetal neurosonography: Reconstructing cerebral midline anatomy and anomalies using a novel three-dimensional ultrasound technique. Prenat Diagn. 2014;34(1):75-83.
- Tukei VJ, Hoffman HJ, Greenberg L, et al. Adverse pregnancy outcomes among HIV-positive women in the era of universal antiretroviral therapy remain elevated compared with HIV-negative women. Pediatr Infect Dis J. 2021;40(9):821-826.
- Turan OM, Bozkurt S, Turan S. Imaging of the placenta. Clin Obstet Gynecol. 2025;68(1):72-85.
- Verkleij CPM, van Oppen ACC, Mulder EJH, et al. Evaluation of antenatal umbilical coiling index at 16-21 weeks of gestation as a predictor of trisomy 21 and other chromosomal defects. Ultrasound Obstet Gynecol. 2013;42(5):545-552.
- Votino C, Cos T, Abu-Rustum R, et al. Use of spatiotemporal image correlation at 11-14 weeks' gestation. Ultrasound Obstet Gynecol. 2013;42(6):669-678.
- Wagner RK, Calhoun BC. The routine obstetric ultrasound examination. Obstet Gynecol Clin North Am. 1998;25(3):451-463.
- Wax J, Minkoff H, Johnson A. Consensus report on the detailed fetal anatomic ultrasound examination: Indications, components, and qualifications. J Ultrasound Med. 2014; 33:189-195.
- Wax JR, Benacerraf BR, Copel J, et al. Consensus Report on the 76811 Scan: Modification. J Ultrasound Med. 2015t;34(10):1915.
- Whitworth M, Bricker L, Neilson JP, Dowswell T. Ultrasound for fetal assessment in early pregnancy. Cochrane Database Syst Rev. 2010;(4):CD007058.
- Williams PL, Crain M, Yildirim C, et al; or the Pediatric HIV/AIDS Cohort Study. Congenital anomalies and in utero antiretroviral exposure in HIV-exposed uninfected infants. JAMA Pediatr. 2015;169(1):48-55.
- Witters I, Meylaerts L, Peeters H, et al. Fetal hydrometrocolpos, uterus didelphys with low vaginal and anal atresia: Difficulties in differentiation from a complex cloacal malformation: A case report. Genet Couns. 2012;23(4):513-517.
- Woelfer B, Salim R, Banerjee S, et al. Reproductive outcomes in women with congenital uterine anomalies detected by three-dimensional ultrasound screening. Obstet Gynecol. 2001;98(6):1099-103.
- Yagel S, Cohen SM, Messing B, Valsky DV. Three-dimensional and four-dimensional ultrasound applications in fetal medicine. Curr Opin Obstet Gynecol. 2009;21(2):167-174.
- Youssef A, Cavalera M, Azzarone C, et al. The use of lung ultrasound during the COVID-19 pandemic: A narrative review with specific focus on its role in pregnancy. J Popul Ther Clin Pharmacol. 2020;27(S Pt 1):e64-e75.
- Zalel Y, Weisz B, Gamzu R, Schiff E, Shalmon B, Achiron R. Chorioangiomas of the placenta: Sonographic and Doppler flow characteristics. J Ultrasound Med. 2002;21(8):909-913.
- Zangen R, Boldes R, Yaffe H, Schwed P, Weiner Z. Umbilical cord cysts in the second and third trimesters: Significance and prenatal approach. Ultrasound Obstet Gynecol. 2010;36(3):296-301.
