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Do We Need to Restrict the Use of Doppler Ultrasound in the First Trimester of Pregnancy?

      Introduction

      During the past decade, an increasing interest in using Doppler ultrasound in the first trimester of pregnancy could be noticed among clinicians who perform fetal ultrasound for estimation of the risk for aneuploidies and for diagnosis of fetal malformations. Considering the potential for high-output ultrasound energy levels in color and spectral Doppler modes and the sometimes lengthy examination time, this new clinical application might expose the fetus to Doppler ultrasound during its early development when it is sensitive to external influences. Therefore, it is important to carefully evaluate the risk-benefit relationship before Doppler ultrasound is used widely in early gestation.
      In Summer 2009, a group of experts on bioeffects and safety aspects of diagnostic ultrasound met for a 3-day workshop
      Participants in the 2009 workshop in Estes Park, CO, USA: John Abbott, Jacques Abramowicz, Stan Barnett, Michel Claudon, Diane Dalecki, Karel Maršál, Doug Miller and Marvin Ziskin.
      to discuss the use of Doppler ultrasound in early pregnancy. This workshop provided a platform for further work by the World Federation for Ultrasound in Medicine and Biology (WFUMB) Safety Committee that resulted in recommendations for the use of Doppler ultrasound in the first trimester of pregnancy, approved by the WFUMB and the International Society for Ultrasound in Obstetrics and Gynecology (http://wfumb.org/about/statements.aspx). The following text summarizes the background information and rationale for these recommendations.

      The Argument for the Use of Fetal Doppler Ultrasound in the First Trimester of Pregnancy

      During the embryonic period, the human heart develops in the cardiogenic plate derived from the splanchnopleuric mesoderm. Three weeks after conception (i.e., 5 wk after the first day of the last menstrual period), the primitive heart tube starts to pulsate. In the subsequent development the heart tube grows and bends, septa begin to grow, the four chambers are formed and, finally, the two outflow tracts separate. At 8 wk after conception, the development of the heart is completed.
      On a transvaginal ultrasound scan, the heart activity can be identified in the real-time 2-D image of the pregnant uterus when the crown-rump length of the embryo is ≥5 mm. This occurs at 5 wk 3 d to 6 wk 3 d of gestational age, calculated from the last menstrual period. After 6 wk of gestation, spectral and color Doppler signals of pulsating blood flow in the fetal heart and large vessels can be detected. During the latter part of the first trimester of pregnancy, ultrasound imaging and Doppler recording can be performed transabdominally.
      Obstetric ultrasound examinations to detect fetal developmental disorders are usually performed in the second trimester of pregnancy. During the past decade, technical developments have profoundly improved the resolution of ultrasound images, thus enabling detection of fetal anomalies at 11–13 wk with high accuracy (
      • Becker R.
      • Wegner R.D.
      Detailed screening for fetal anomalies and cardiac defects at the 11-13-week scan.
      ;
      • Ndumbe F.M.
      • Navti O.
      • Chilaka V.N.
      • Konje J.C.
      Prenatal diagnosis in the first trimester of pregnancy.
      ). The first reports of ultrasound detection in the first trimester of the fluid collection in the nuchal region of fetuses with trisomy 21 (
      • Bronshtein M.
      • Rottem S.
      • Yoffe N.
      • Blumenfeld Z.
      First-trimester and early second-trimester diagnosis of nuchal cystic hygroma by transvaginal sonography: diverse prognosis of the septated from the nonseptated lesion.
      ;
      • Cullen M.T.
      • Gabrielli S.
      • Green J.J.
      • Rizzo N.
      • Mahoney M.J.
      • Salafia C.
      • Bovicelli L.
      • Hobbins J.C.
      Diagnosis and significance of cystic hygroma in the first trimester.
      ) showed that by measuring the nuchal translucency (NT) thickness with ultrasound, it is possible to screen for fetuses with aneuploidies (trisomies 21, 13 and 18) at this time of gestation (
      • Nicolaides K.H.
      • Brizot M.L.
      • Snijders R.J.
      Fetal nuchal translucency: ultrasound screening for fetal trisomy in the first trimester of pregnancy.
      ). Furthermore, the increased NT was found to be associated with cardiac defects (
      • Hyett J.
      • Perdu M.
      • Sharland G.
      • Snijders R.
      • Nicolaides K.H.
      Using fetal nuchal translucency to screen for major congenital cardiac defects at 10-14 weeks of gestation: population based cohort study.
      ). Screening for Down syndrome and other major aneuploidies at 11 wk to 13 wk 6 d of gestation, using NT measurement in combination with maternal age and analysis of biochemical markers in maternal serum (pregnancy-associated protein-A and free β-human chorionic gonadotrophin), was reported to have a detection rate of ∼90%, with a false positive rate of 5% (including a necessity for an invasive procedure, such as chorion villi biopsy or amniocentesis;
      • Ndumbe F.M.
      • Navti O.
      • Chilaka V.N.
      • Konje J.C.
      Prenatal diagnosis in the first trimester of pregnancy.
      ;
      • Nicolaides K.H.
      Screening for fetal aneuploidies at 11 to 13 weeks.
      ). Currently in many countries and regions, the ultrasound measurement of NT is offered routinely to pregnant women as a way of estimating the risk for chromosomal abnormalities.
      In 1998, the first studies were published demonstrating that a large proportion of fetuses with aneuploidies have abnormal blood flow pattern in the ductus venosus as recorded using spectral Doppler ultrasound (
      • Borrell A.
      • Antolin E.
      • Costa D.
      • Farre M.T.
      • Martinez J.M.
      • Fortuny A.
      Abnormal ductus venosus blood flow in trisomy 21 fetuses during early pregnancy.
      ;
      • Matias A.
      • Gomes C.
      • Flack N.
      • Montenegro N.
      • Nicolaides K.H.
      Screening for chromosomal abnormalities at 10-14 weeks: the role of ductus venosus blood flow.
      ). The ductus venosus (DV) is a vessel that is present during fetal life and connects the umbilical vein to the inferior vena cava. Normally the DV flow is pulsatile, with positive blood velocities throughout the cardiac cycle. In up to 90% of aneuploid fetuses, the wave corresponding to atrial contraction (A wave) is absent or reversed (
      • Matias A.
      • Gomes C.
      • Flack N.
      • Montenegro N.
      • Nicolaides K.H.
      Screening for chromosomal abnormalities at 10-14 weeks: the role of ductus venosus blood flow.
      ). The finding of abnormal DV flow in fetuses with trisomies has been confirmed in several studies (
      • Borrell A.
      The ductus venosus in early pregnancy and congenital anomalies.
      ). It has also been reported that aneuploid fetuses have an increased frequency of tricuspid regurgitation (
      • Falcon O.
      • Faiola S.
      • Huggon I.
      • Allan L.
      • Nicolaides K.H.
      Fetal tricuspid regurgitation at the 11 + 0 to 13 + 6-week scan: association with chromosomal defects and reproducibility of the method.
      ;
      • Huggon I.C.
      • De Figueiredo D.B.
      • Allan L.D.
      Tricuspid regurgitation in the diagnosis of chromosomal anomalies in the fetus at 11-14 weeks of gestation.
      ). Furthermore, the results of Doppler ultrasound examinations of other fetal vessels indicate associations between the abnormal findings in hepatic arteries (increased flow) and Down syndrome (
      • Bilardo C.M.
      • Timmerman E.
      • De Medina P.G.
      • Clur S.A.
      Low-resistance hepatic artery flow in first-trimester fetuses: an ominous sign.
      ), the intra-abdominal section of the umbilical vein (decreased flow) and subsequent development of intrauterine growth restriction (
      • Rizzo G.
      • Capponi A.
      • Pietrolucci M.E.
      • Capece A.
      • Arduini D.
      First-trimester umbilical vein blood flow in pregnancies with low serum pregnancy-associated plasma protein-A levels: an early predictor of fetal growth restriction.
      ) and abnormal DV flow and complications in monochorionic twin pregnancies (
      • Matias A.
      • Montenegro N.
      • Loureiro T.
      • Cunha M.
      • Duarte S.
      • Freitas D.
      • Severo M.
      Screening for twin-twin transfusion syndrome at 11-14 weeks of pregnancy: the key role of ductus venosus blood flow assessment.
      ).
      In first-trimester fetuses with normal chromosomes (euploid fetuses), an increased NT (
      • Hyett J.
      • Perdu M.
      • Sharland G.
      • Snijders R.
      • Nicolaides K.H.
      Using fetal nuchal translucency to screen for major congenital cardiac defects at 10-14 weeks of gestation: population based cohort study.
      ) and an abnormal DV Doppler finding (
      • Matias A.
      • Huggon I.
      • Areias J.C.
      • Montenegro N.
      • Nicolaides K.H.
      Cardiac defects in chromosomally normal fetuses with abnormal ductus venosus blood flow at 10-14 weeks.
      ) might indicate an increased risk for cardiac defects. This risk was subsequently confirmed by the same research group in a larger patient cohort. The authors proposed that Doppler assessment of the DV flow pattern might improve the results of screening for cardiac malformations (
      • Chelemen T.
      • Syngelaki A.
      • Maiz N.
      • Allan L.
      • Nicolaides K.H.
      Contribution of ductus venosus Doppler in first-trimester screening for major cardiac defects.
      ).

      The Argument Against the Use of Fetal Doppler Ultrasound in the First Trimester of Pregnancy

      Ultrasound energy considerations

      B-mode and Doppler ultrasound imaging use different pulsing regimes with consequent different power outputs. When considering the potential for harmful thermal effects, it is the spatial peak temporal average intensity (ISPTA) that is important. Past surveys showed that this intensity was considerably higher in pulsed Doppler or color-flow modes than in B-mode (
      • Whittingham T.A.
      The acoustic output of diagnostic machines.
      ). A more recent survey, based on outputs declared by manufacturers (
      • Martin K.
      The acoustic safety of new ultrasound technologies.
      ), shows that there is considerable overlap in these values between modes, but the mean intensity remains higher for the pulsed Doppler and color-flow modes. The median intensity for B-mode (273 mW/cm2) is 36% of that for pulsed Doppler and 61% of the mean for color-flow imaging. The range of reported intensities is shown in Figure 1. Both transabdominal and transvaginal probes are included in this survey.
      Figure thumbnail gr1
      Fig. 1Range of spatial peak temporal average intensities reported by manufacturers of ultrasound scanners. It is these intensities that have the most relevance for thermal effects. The median values are also shown.
      (Adapted from
      • Martin K.
      The acoustic safety of new ultrasound technologies.
      .)
      Modern scanners display safety-related information in the form of mechanical and thermal indices. These indices are defined in the Output Display Standard, a document produced jointly by the
      • American Institute of Ultrasound in Medicine
      • National Electrical Manufacturers Association
      Standard for real-time display of thermal and mechanical acoustic output indices on diagnostic ultrasound equipment.
      . The thermal index (TI) gives an indication of the temperature rise that might be expected in tissue during the acquisition of the scan on the screen, whereas the mechanical index (MI) reflects the potential for mechanical effects such as cavitation. There are three forms of TI: soft tissue thermal index (TIS) reflects the temperature rise in soft tissue, bone thermal index (TIB) reflects the temperature when the ultrasound focus coincides with bone, and cranial thermal index (TIC) reflects when there is bone close to the skin (e.g., in the neonatal skull). The British Medical Ultrasound Society has issued guidelines for the safe use of clinical ultrasound based on these indices (www.bmus.org). The guidelines state that TIS should be monitored up to 10 wk after the last menstrual period, and TIB should be monitored thereafter. Once the TI exceeds 0.7, the scanning time should be limited. For example, scanning times less than 15 min are recommended for 1.5< TI <2 (Table 1).
      Table 1Recommended exposure time for Doppler ultrasound examinations during pregnancy
      Thermal index
      Monitor thermal index for soft tissue up to 10 gestational wk after the last menstrual period, and thermal index for bones thereafter. Adapted from the British Medical Ultrasound Society guidelines for the safe use of clinical ultrasound (www.bmus.org).
      Maximum exposure time for an embryo or fetusComment
      ≤0.7UnlimitedRecommended range provided adequate images/signals can be obtained
      >0.7–1.060 minObserve ALARA
      >1.0–1.530 minObserve ALARA
      >1.5–2.015 minObserve ALARA
      >2.0–2.54 minObserve ALARA
      >2.5–3.01 minObserve ALARA
      >3.0Not recommendedNot to be used for obstetric scanning
      ALARA = output energy as low as reasonably achievable.
      Monitor thermal index for soft tissue up to 10 gestational wk after the last menstrual period, and thermal index for bones thereafter. Adapted from the British Medical Ultrasound Society guidelines for the safe use of clinical ultrasound (www.bmus.org).

      Recently reported bioeffect studies

      Three recent studies have investigated the effects of ultrasound on the fetus and embryo.
      • Ang Jr., E.S.
      • Gluncic V.
      • Duque A.
      • Schafer M.E.
      • Rakic P.
      Prenatal exposure to ultrasound waves impacts neuronal migration in mice.
      studied the effects on neuronal migration in the cerebral cortex in the embryonic mouse of exposure to ultrasound for 4 min up to 7 h. The animals were exposed on the final 3 days of pregnancy (days 16–19) and were euthanized on the 10th postnatal day. Analysis of the brains of >335 pups showed that, when exposed to ultrasound for a total of 30 min or longer, a small but statistically significant number of neurons failed to reach their proper position in the brain. The amount of faulty dispersion of labeled neurons increased with the duration of exposure to ultrasound. There was also an increase in abnormal cell migration in animals exposed to a 420-min sham experiment over that in normal controls. This finding might be the result of stress experienced by pregnant animals during prolonged exposure to the experimental procedure. Shorter durations of sham exposure had no effect on cell migration compared with normal controls. In an independent sham-exposure experiment, ultrasound exposure did not affect oxygenation or body core temperature in pregnant mice; therefore, the authors speculate that the mechanism for the disturbed neuronal migration resulting from ultrasound is a nonthermal, noncavitational, mechanically mediated effect, perhaps involving radiation force, microstreaming or shear effects on cellular walls. These mechanical effects might interfere with the delicate adhesion between the migratory neurons and the surface of migratory substrates, such as the radial glial shafts, which serve as guides.
      • Schneider-Kolsky M.E.
      • Ayobi A.
      • Lombardo P.
      • Brown D.
      • Kedang B.
      • Gibbs M.E.
      Ultrasound exposure of the foetal chick brain: effects on learning and memory.
      investigated whether the effects of B-mode or pulsed Doppler-mode ultrasound close to the time of hatching could affect memory in newly hatched chicks. The results suggest that extended exposure to pulsed Doppler ultrasound could adversely affect cognitive function in the chick. The chick brains were exposed on day 19 of a 21-d incubation period to a 5- or 10-min sham ultrasound examination, 5 or 10 min of B-mode ultrasound, or to 1, 2, 3, 4 or 5 min of pulsed Doppler ultrasound in ovo. The derated ISPTA of the clinical transducer used was 97.2 mW/cm2 for B-mode and 576 mW/cm2 for pulsed Doppler mode. The TI was 0.1, and MI was between 0.39 and 0.55. Learning and memory function (shown by a discrimination task) were assessed 2 d after hatching. The chicks were exposed to red or blue beads, the red ones being drenched with a bitter fluid. Chicks quickly learned to associate the red color with a bitter taste. In addition, if memory formation proceeded normally, they would avoid pecking at red beads in future tests. B-mode exposures of up to 10 min did not impair memory function in the chick model, whereas exposure to pulsed Doppler ultrasound lasting ≥4 min resulted in significant deficits in long-term memory. Short-term and intermediate-term memory were significantly impaired after 5 min of exposure to Doppler ultrasound, as was the ability to relearn.
      The aim of the study by
      • Pellicer B.
      • Herraiz S.
      • Ta’Boas E.
      • Felipo V.
      • Simon C.
      Ultrasound bioeffects in rats: quantification of cellular damage in the fetal liver after pulsed Doppler imaging.
      was to investigate whether pulsed Doppler exposure of the DV in fetal rats could cause damage to their livers, as assessed using the cleaved caspase 3 apoptosis test. This study is important because in clinical practice, markers for Down syndrome measured with Doppler in early pregnancy include blood flow in small vessels, such as the DV and across the tricuspid valve. Pregnant female rats (gestational day 18) were anesthetized, and fetuses in the proximal position from each uterine horn were exposed to ultrasound. Pulsed wave and color Doppler from a clinical ultrasound scanner were used. For the pulsed Doppler exposures, a frequency of 5.8 MHz and a frame rate of 26.5 Hz were used. The sample volume was 0.5 mm. Under these conditions, the derated ISPTA given by the manufacturer was said to be 40.6 mW/cm2. The insonation angle was kept at <30 degrees. MI and TI were <1. Color Doppler was used to identify the first fetus in the right uterine horn and its DV on a median sagittal plane or an oblique transverse abdominal plane. Fetal DVs were exposed to pulsed Doppler for 3–600 s to establish the minimum exposure time leading to cellular damage. The mothers were sacrificed 2–24 h after exposure. Significant apoptosis was seen in all livers of fetuses sacrificed at 7 h and exposed for 20 s or longer. For animals exposed for longer than 300 s, this effect was visible after 4 h. A linear relationship between apoptotic activity and pulsed Doppler scanning time was found; the longer the exposure time, the more liver cell damage was found. This damage disappeared over time, with no liver showing damage when an animal was sacrificed 12 or 24 h after exposure, thus indicating a transient effect. In this study, no effect was found for exposure times of 10 s or shorter. Based on this finding, the authors recommend that Doppler investigations be restricted to as short a time as possible, and that repeated Doppler scans should be spaced as far apart as possible if undertaken within 24 hours.
      Although all three of these studies have their limitations, and the relevance to human embryonic and fetal exposure levels is difficult to determine, the studies indicate that there is the possibility that subtle effects might be induced by commercial clinical ultrasound scanners. All three studies have demonstrated a relationship between length of exposure to Doppler ultrasound and potentially irreversible biological effects. Although there is uncertainty about the biological effects that can be induced by pulsed Doppler exposures of the embryo or fetus, it is particularly important to observe the ALARA (as low as reasonably achievable) principle.

      First-Trimester Doppler in Screening for Aneuploidies: Does the Benefit Outweigh the Risk?

      By including additional ultrasound markers (e.g., the absence of nasal bone) into the models of first-trimester screening for fetal aneuploidies, it is possible to achieve detection rates exceeding 90% with false-positive rates of 5% or less (
      • Cicero S.
      • Curcio P.
      • Papageorghiou A.
      • Sonek J.
      • Nicolaides K.
      Absence of nasal bone in fetuses with trisomy 21 at 11-14 weeks of gestation: an observational study.
      ). A similar effect was reported when Doppler examinations of the DV or tricuspid valve, or both, were incorporated into the screening models (
      • Kagan K.O.
      • Valencia C.
      • Livanos P.
      • Wright D.
      • Nicolaides K.H.
      Tricuspid regurgitation in screening for trisomies 21, 18 and 13 and Turner syndrome at 11+0 to 13+6 weeks of gestation.
      ;
      • Maiz N.
      • Valencia C.
      • Kagan K.O.
      • Wright D.
      • Nicolaides K.H.
      Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation.
      ).
      By various combinations of biochemical tests and ultrasound markers, several models have been developed for estimating the risk for trisomy 21 in the first trimester of pregnancy (Table 2). The combination of maternal age and biochemical markers in maternal serum gives a relatively low detection rate. Including ultrasound measurements of the NT thickness in the models significantly improves the efficacy of the test (
      • Kagan K.O.
      • Valencia C.
      • Livanos P.
      • Wright D.
      • Nicolaides K.H.
      Tricuspid regurgitation in screening for trisomies 21, 18 and 13 and Turner syndrome at 11+0 to 13+6 weeks of gestation.
      ;
      • Maiz N.
      • Valencia C.
      • Kagan K.O.
      • Wright D.
      • Nicolaides K.H.
      Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation.
      ). Recently, a model combining NT and biochemical tests in two steps gave a detection rate of 92% and a false-positive rate 1.4% (
      • Habayeb O.
      • Goodburn S.
      • Chudleigh T.
      • Brockelsby J.
      • Missfelder-Lobos H.
      • Hackett G.
      • Lees C.
      The NTplus method of screening for Down syndrome: achieving the 2010 targets?.
      ). By performing Doppler examination of flow in the DV or tricuspid valve, or both, in all fetuses, detection rates of 96% were achieved (
      • Kagan K.O.
      • Valencia C.
      • Livanos P.
      • Wright D.
      • Nicolaides K.H.
      Tricuspid regurgitation in screening for trisomies 21, 18 and 13 and Turner syndrome at 11+0 to 13+6 weeks of gestation.
      ;
      • Maiz N.
      • Valencia C.
      • Kagan K.O.
      • Wright D.
      • Nicolaides K.H.
      Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation.
      ). However, using the Doppler measurements in a contingent manner, (i.e., in a preselected group of pregnancies with intermediate risk for aneuploidy [risk 1:51 to 1:1000]) on the basis of the first line screening (maternal age, NT, fetal heart rate and serum biochemistry) gave almost identical results. Detection rates in this case were 96% for tricuspid regurgitation and 97% for DV with false-positive rates of 2.6% and 2.4%, respectively (
      • Kagan K.O.
      • Valencia C.
      • Livanos P.
      • Wright D.
      • Nicolaides K.H.
      Tricuspid regurgitation in screening for trisomies 21, 18 and 13 and Turner syndrome at 11+0 to 13+6 weeks of gestation.
      ;
      • Maiz N.
      • Valencia C.
      • Kagan K.O.
      • Wright D.
      • Nicolaides K.H.
      Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation.
      ). In the latter two models, if DV or tricuspid valve measurements were included as the second line test, only 15% of pregnant women were exposed to Doppler ultrasound in the first trimester (Table 2). In contrast, if biochemical markers are used only as the secondary test, the whole population would be exposed to Doppler examinations as a part of the first line screening (
      • Kagan K.O.
      • Staboulidou I.
      • Cruz J.
      • Wright D.
      • Nicolaides K.H.
      Two-stage first trimester screening for trisomy 21 by ultrasound assessment and biochemical testing.
      ).
      Table 2Efficacy of first-trimester screening for trisomy 21
      Screening modelFalse-positive rate (%)Detection rate (%)Exposure to Doppler ultrasound (% of population)Reference
      MA + biochemical tests
      Biochemical tests: maternal serum free β-human chorionic gonadotrophin and pregnancy-associated plasma protein-A.
      4.8620
      • Kagan K.O.
      • Staboulidou I.
      • Cruz J.
      • Wright D.
      • Nicolaides K.H.
      Two-stage first trimester screening for trisomy 21 by ultrasound assessment and biochemical testing.
      MA + NT1.9760
      • Kagan K.O.
      • Staboulidou I.
      • Cruz J.
      • Wright D.
      • Nicolaides K.H.
      Two-stage first trimester screening for trisomy 21 by ultrasound assessment and biochemical testing.
      MA + NT + biochemical tests2.3890
      • Kagan K.O.
      • Staboulidou I.
      • Cruz J.
      • Wright D.
      • Nicolaides K.H.
      Two-stage first trimester screening for trisomy 21 by ultrasound assessment and biochemical testing.
      MA + NT + FHR + biochemical tests5940
      • Maiz N.
      • Valencia C.
      • Kagan K.O.
      • Wright D.
      • Nicolaides K.H.
      Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation.


      • Kagan K.O.
      • Valencia C.
      • Livanos P.
      • Wright D.
      • Nicolaides K.H.
      Tricuspid regurgitation in screening for trisomies 21, 18 and 13 and Turner syndrome at 11+0 to 13+6 weeks of gestation.
      Model 4 + DV597100
      • Maiz N.
      • Valencia C.
      • Kagan K.O.
      • Wright D.
      • Nicolaides K.H.
      Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation.
      Model 4 + TD596100
      • Kagan K.O.
      • Valencia C.
      • Livanos P.
      • Wright D.
      • Nicolaides K.H.
      Tricuspid regurgitation in screening for trisomies 21, 18 and 13 and Turner syndrome at 11+0 to 13+6 weeks of gestation.
      Contingent DV screening (model 4 as the first line screening)
      Contingent screening: a subgroup of pregnancies with intermediate risk for aneuploidy (1:51–1:1000) according to the first-line screening is submitted to the second-line test.
      2.69615
      • Maiz N.
      • Valencia C.
      • Kagan K.O.
      • Wright D.
      • Nicolaides K.H.
      Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation.
      Contingent TD screening (model 4 as the first line screening)2.49615
      • Kagan K.O.
      • Valencia C.
      • Livanos P.
      • Wright D.
      • Nicolaides K.H.
      Tricuspid regurgitation in screening for trisomies 21, 18 and 13 and Turner syndrome at 11+0 to 13+6 weeks of gestation.
      Contingent biochemical screening (MA + NT + nasal bone as the first line screening)2.6900
      • Kagan K.O.
      • Staboulidou I.
      • Cruz J.
      • Wright D.
      • Nicolaides K.H.
      Two-stage first trimester screening for trisomy 21 by ultrasound assessment and biochemical testing.
      Contingent biochemical screening (MA + NT + DV as the first line screening)2.796100
      • Kagan K.O.
      • Staboulidou I.
      • Cruz J.
      • Wright D.
      • Nicolaides K.H.
      Two-stage first trimester screening for trisomy 21 by ultrasound assessment and biochemical testing.
      Contingent biochemical screening (MA + NT + TD as the first line screening)2.694100
      • Kagan K.O.
      • Staboulidou I.
      • Cruz J.
      • Wright D.
      • Nicolaides K.H.
      Two-stage first trimester screening for trisomy 21 by ultrasound assessment and biochemical testing.
      DV = ductus venosus Doppler; FHR = fetal heart rate; MA = maternal age; NT = fetal nuchal translucency; TD = tricuspidal valve Doppler.
      Reports are from the King’s College Hospital research group based on retrospective application of various screening models on a series of 19,614 pregnancies.
      Biochemical tests: maternal serum free β-human chorionic gonadotrophin and pregnancy-associated plasma protein-A.
      Contingent screening: a subgroup of pregnancies with intermediate risk for aneuploidy (1:51–1:1000) according to the first-line screening is submitted to the second-line test.

      Safe Use of Doppler Ultrasound in the First Trimester of Pregnancy

      To be able to follow the ALARA principle, the ultrasound operator must be able to understand the information provided about ultrasound energy exposure, to know where to find it and how to control the energy emitted by the ultrasound equipment. Unfortunately, it has been shown clearly that such knowledge is anything but satisfactory among the experts on fetal ultrasound in Europe (
      • Maršál K.
      The output display standard: has it missed its target.
      ), the United States (
      • Houston L.E.
      • Allsworth J.
      • Macones G.A.
      Ultrasound is safe. right? Resident and maternal-fetal medicine fellow knowledge regarding obstetric ultrasound safety.
      ;
      • Sheiner E.
      • Shoham-Vardi I.
      • Abramowicz J.S.
      What do clinical users know regarding safety of ultrasound during pregnancy?.
      ) and in Asia (
      • Akhtar W.
      • Arain M.A.
      • Ali A.
      • Manzar N.
      • Sajjad Z.
      • Memon M.
      • Memon W.
      • Ahmad N.
      Ultrasound biosafety during pregnancy: what do operators know in the developing world? National survey findings from Pakistan.
      ). Without a doubt, there is a need for intensified continuous education of ultrasound users in questions of ultrasound safety. The international and national societies of medical ultrasound must coordinate their teaching efforts and provide guidelines for the safe use of diagnostic ultrasound and especially of Doppler ultrasound in pregnancy.
      One possible way to encourage the ultrasound users, especially those using Doppler ultrasound in the first trimester, to acquire the necessary knowledge of safety issues is to require adequate reporting of the information on ultrasound exposure when submitting reports on research studies to scientific journals or to congresses (
      • Campbell S.
      • Platt L.
      The publishing of papers on first-trimester Doppler.
      ;
      • ter Haar G.
      • Shaw A.
      • Pye S.
      • Ward B.
      • Bottomley F.
      • Nolan R.
      • Coady A.M.
      Guidance on reporting ultrasound exposure conditions for bio-effects studies.
      ). Better adherence to the guidelines would then be expected (
      • Salvesen K.A.
      • Lees C.
      Ultrasound is not unsound, but safety is an issue.
      ). If Doppler ultrasound were used properly, including safety considerations in the research context, then it might be expected that such practice would also be carried over into clinical implementation of research results in patient care.
      There are a few studies that have evaluated the levels of TI and MI and the exposure time during standard obstetric ultrasound examinations (
      • Deane C.
      • Lees C.
      Doppler obstetric ultrasound: A graphical display of temporal changes in safety indices.
      ;
      • Sheiner E.
      • Freeman J.
      • Abramowicz J.S.
      Acoustic output as measured by mechanical and thermal indices during routine obstetric ultrasound examinations.
      ,
      • Sheiner E.
      • Shoham-Vardi I.
      • Pombar X.
      • Hussey M.J.
      • Strassner H.T.
      • Abramowicz J.S.
      An increased thermal index can be achieved when performing Doppler studies in obstetric sonography.
      ). These studies have shown that the TI values occasionally exceed 2.0 when color or spectral pulsed wave Doppler modes are applied. This is despite the fact that in most obstetric examinations, fully satisfactory images and/or Doppler signals can be obtained at low levels of TI and MI. The surveys cited in this article were performed for examinations in the second half of pregnancy; to our knowledge, no such surveys have been performed for Doppler examinations in the first trimester.
      To adhere to the recommendation of TI ≤1.0 for Doppler use in the fetal examination at 11 wk to 13 wk and 6 d (
      • Salvesen KÅ
      • Lees C.
      • Abramowicz J.
      • Brezinka C.
      • ter Haar G.
      • Maršál K.
      Safe use of Doppler ultrasound during the 11 to 13 + 6-week scan: Is it possible?.
      ), the ultrasound operator must control the factors that influence ultrasound exposure. In brief, the following influence output energy in color Doppler mode: the width of the color box, how deep the box is located, and the color scale. For spectral pulsed wave Doppler, the corresponding factors are the velocity scale related to the pulse repetition frequency and the depth location of the sample volume (gate). For both color and spectral Doppler, there are overall output intensity (power) controls. The recommended procedure is always to use low default output settings and only to consider an increase in the overall output energy when optimization of the “receive parameters” of the image and Doppler signals does not give satisfactory results.
      The duration of an examination is important for the resulting ultrasound exposure. According to practical experience, most Doppler examinations indicated in the first trimester can be performed within 5–10 min, as has been recommended in the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) statement (
      • Salvesen KÅ
      • Lees C.
      • Abramowicz J.
      • Brezinka C.
      • Ter Haar G.
      • Maršál K.
      Board of International Society of Ultrasound in Obstetrics and Gynecology (ISUOG). ISUOG statement on the safe use of Doppler in the 11 to 13 +6-week fetal ultrasound examination.
      ). However, on some occasions it may be difficult to receive good signals from the tiny vessel structures of the first trimester fetus. For example, if the reason is the obesity of the mother, a controlled and short-lasting increase in the output intensity may be justified; this might enable easier acquisition of good signals and, consequently, shortening of the total examination time. The time needed for a Doppler examination is dependent on the experience and skill of the examiner (
      • Nicolaides K.H.
      Screening for fetal aneuploidies at 11 to 13 weeks.
      ). It has been shown that to achieve a 95% success rate in examining the DV in early pregnancy, on average a minimum of 80 examinations is necessary (
      • Maiz N.
      • Kagan K.O.
      • Milovanovic Z.
      • Celik E.
      • Nicolaides K.H.
      Learning curve for Doppler assessment of ductus venosus flow at 11 + 0 to 13 + 6 weeks’ gestation.
      ). Thus, extensive supervised training is needed, which in itself speaks against including the DV and tricuspid valve examinations as a routine part of all screening examinations in the first trimester.
      As mentioned earlier, a properly indicated Doppler examination of fetuses in early gestation can give important and clinically useful results. Applied to all pregnancies as a routine part of the screening for fetal aneuploidies, DV and tricuspid valve Doppler studies can increase the detection rate of Down syndrome. However, fully comparable results have been obtained when Doppler examinations were applied in a contingent model as the second-line test in preselected pregnancies with intermediate risk for aneuploidy (Table 1;
      • Kagan K.O.
      • Staboulidou I.
      • Cruz J.
      • Wright D.
      • Nicolaides K.H.
      Two-stage first trimester screening for trisomy 21 by ultrasound assessment and biochemical testing.
      ;
      • Maiz N.
      • Valencia C.
      • Kagan K.O.
      • Wright D.
      • Nicolaides K.H.
      Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11-13 weeks of gestation.
      ;
      • Nicolaides K.H.
      Screening for fetal aneuploidies at 11 to 13 weeks.
      ). This application is preferable for safety reasons. It should also be mentioned that, probably in the near future, the screening for chromosomal defects in early gestation might be based on a completely different concept (e.g., on analysis of the free fetal DNA in maternal blood;
      • Ehrich M.
      • Deciu C.
      • Zwiefelhofer T.
      • Tynan J.A.
      • Cagasan L.
      • Tim R.
      • Lu V.
      • McCullough R.
      • McCarthy E.
      • Nygren A.O.
      • Dean J.
      • Tang L.
      • Hutchison D.
      • Lu T.
      • Wang H.
      • Angkachatchai V.
      • Oeth P.
      • Cantor C.R.
      • Bombard A.
      • van den Boom D.
      Noninvasive detection of fetal trisomy 21 by sequencing of DNA in maternal blood: a study in a clinical setting.
      ;
      • Hahn S.
      • Lapaire O.
      • Tercanli S.
      • Kolla V.
      • Hösli I.
      Determination of fetal chromosome aberrations from fetal DNA in maternal blood: has the challenge finally been met?.
      ), thus making biochemical and ultrasound screening for aneuploidies superfluous. One recent report has shown that the first-trimester Doppler might improve the early detection of cardiac defects (
      • Chelemen T.
      • Syngelaki A.
      • Maiz N.
      • Allan L.
      • Nicolaides K.H.
      Contribution of ductus venosus Doppler in first-trimester screening for major cardiac defects.
      ), which would be desirable. The safety aspects and the necessity of expertise for execution of these examinations again speak against an application of Doppler in early pregnancy as a routine part of screening for cardiac defects. Doppler ultrasound will probably be useful as the second-line examination in high-risk fetuses, such as those with normal chromosomes and increased NT.
      The consideration presented here, regarding the use of Doppler ultrasound in the first trimester, provides the background to the joint WFUMB-ISUOG statement on the safe use of Doppler in the fetal ultrasound examination at 11 wk to 13 wk and 6 d. The Bioeffects and Safety Committee of the ISUOG, in their recent opinion article, summarized these concerns as follows: “The main reason for advocating precautionary use of Doppler ultrasound in early gestation is not because we know that it causes harm, but because we don’t know that it is safe, and because the first trimester is a particularly vulnerable period of fetal life” (
      • Sheiner E.
      • Shoham-Vardi I.
      • Pombar X.
      • Hussey M.J.
      • Strassner H.T.
      • Abramowicz J.S.
      An increased thermal index can be achieved when performing Doppler studies in obstetric sonography.
      ).

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