Taipale, Pekka MD, PhD; Ämmälä, Martti MD; Salonen, Riitta MD, PhD; Hiilesmaa, Vilho MD, PhD
Ultrasonography during early pregnancy is traditionally carried out for assessment of gestational age, identification of nonviable pregnancies, and detection of twins.1 More recently, screening for fetal chromosomal abnormalities by observation of increased nuchal translucency thickness has gained popularity.2,3 Improved resolution and the advent of vaginal probes have facilitated evaluation of most fetal structures in early pregnancy.4–6
Attempts during the first trimester to detect fetal disorders, other than those associated with increased nuchal translucency thickness, have so far mostly been confined to high-risk groups or to selected populations.7–9 There is, however, increasing evidence that early ultrasonography might also be feasible in screening for fetal structural defects in low-risk pregnancies,6,10–14 but experience in large populations is still limited.
In this study, we evaluated the extent to which selected major structural congenital abnormalities of the fetus could be seen in pregnancies of nonselected women, by offering a scan at 13–14 gestational weeks as part of routine antenatal care.
MATERIALS AND METHODS
From January 1993 to December 1998, a total of 23,104 consecutive, nonselected pregnant women agreed to have early screening by transvaginal ultrasonography at Jorvi Hospital, Espoo, Finland. This hospital provides obstetric services to residents of a defined geographic area in the western part of greater Helsinki. The scan was offered at a nominal fee as part of the public health care system used by 99% of pregnant women in the area. A second trimester ultrasound screening was offered on an experimental basis during a short period, from November 1994 to May 1996. Serum screening was not publicly offered, but an unknown number of patients obtained it in the private sector.
All suspected or verified fetal anomalies in the area (found in the public or private sector) were referred to a single unit, the Department of Obstetrics and Gynecology, Helsinki University, where the third and fourth authors (RS and VH) had access to information on further procedures and their outcome. The present study focuses on the performance of the early ultrasonography only, with all results of subsequent diagnostic procedures considered as part of the outcome.
A single ultrasound machine with the same probes was shared by all operators throughout the study period: a Hitachi EUB-420 (Hitachi Medical Corp., Tokyo, Japan) equipped with a 6.5-MHz intravaginal transducer with an angle of 140 degrees and a transabdominal 5-MHz convex transducer.
The scan was scheduled at 13–14 postmenstrual weeks and performed transvaginally, except for those (fewer than 1%) who declined use of the vaginal route. Three percent were also examined transabdominally to enhance visualization of the fundal part of the uterus. The study protocol, including the charge of the scan to the patients (about $20), was accepted by the local ethics committee. The women were counseled regarding the possibility of an abnormal finding, and they gave informed verbal consent to the procedures.
The following 2639 pregnancies were excluded after recruitment: 91 with nonviable pregnancy, 30 with termination for social reasons, 35 with spontaneous abortion, 1684 with 16 or more completed weeks (biparietal diameter greater than 36 mm) and 758 with less than 10 weeks (crown–rump length less than 31 mm) at first attendance, and 41 (0.2%) with an unknown outcome of the pregnancy due to the subject's relocation. The remaining 20,465 mothers with their 20,751 fetuses constituted the study population. There were 283 sets of twins and three triplet pregnancies.
The two first authors (PT and MÄ) performed 10% of the early scans, and the remaining 90% were carried out by a group of five midwives trained in obstetric sonography. Each midwife had performed at least 100 transvaginal and 100 transabdominal examinations under the personal guidance of the first author before starting to scan independently. The first author had done over 3000 similar scans before this study. During 1 working week, each midwife usually spent 1 day for scanning approximately 15 mothers and the remaining days for other tasks. Approximately 1–2 scans daily were referred by a sonographer to the first or the second author for review. After the first year, every sonographer had performed at least 700 examinations, and the same group continued screening during the 6 study years.
The midwives attended quarterly meetings at the Department of Obstetrics and Gynecology of Helsinki University, where fetal anomalies found and missed at screening were reviewed. The first and second authors offered complementary training twice a year at the screening site, using slides and videos. The screeners also attended a national congress related to perinatal ultrasonography approximately once a year.
The scans consisted of measurement of crown–rump length, biparietal diameter, and femur length, followed by systematic evaluation of fetal anatomy against a checklist (Table 1). Abnormal findings not included in this checklist were also recorded. Nuchal translucency was measured, and fetuses with a thickness of 3 mm or more (corresponding to the 99th centile) were referred for counseling and eventual karyotyping.3 About 20 minutes were allocated to each screening session.
If the screener suspected an anomaly, the first or the second author, proficient in obstetric ultrasonography, also examined the patient. When the obstetrician agreed on the possibility of an anomaly, the mother was referred to the Department of Obstetrics and Gynecology, Helsinki University Central Hospital, where she was re-examined and counseled, followed by eventual karyotyping by chorionic villus biopsy or amniocentesis, as appropriate.
To calculate the sensitivity of ultrasonography in identifying fetuses with structural defects, we selected disorders that we considered detectable at a standard screening of low-risk mothers in early pregnancy. These included anomalies of the brain and neural tube, anomalies of the urinary tract, closure defects in the abdominal wall (omphalocele and gastroschisis), absence of one or more long bones, and sacrococcygeal teratoma.
Oral clefts, heart anomalies (left or right heart hypoplasia, ventricular septal defects, transposition of the great arteries), hypospadias, club foot, polydactyly, and ovarian cysts were not expected to be identified in our setting and therefore were not included in the sensitivity calculations.
All terminations and 95% of the deliveries took place either at Jorvi Hospital or at Helsinki University Central Hospital. Information on the outcome of the pregnancies was retrieved from the computerized hospital databases, in which fetal malformations appear both in written form and coded using the International Classification of Diseases, 9th or 10th Revisions. Obstetric and pediatric records were reviewed for those with a diagnosis of malformation. In addition, referrals to neonatal or pediatric units and autopsy reports were also reviewed. The data were completed by information obtained from the Finnish national birth and malformation registries. It is compulsory to report to these registers all structural and chromosomal anomalies up to 1 year of age.15 In 41 pregnancies (0.2%), the outcome could not be traced. A database was created using SAS software (SAS Institute Inc., Cary, NC).
Sensitivities are presented as percentages with their 95% confidence intervals (CIs) calculated by the exact (binomial) method. The χ2 test and the Armitage test for trend in proportions were used to test the variation of sensitivity across the study period. A linear regression line with its 95% confidence limits was constructed to illustrate the trend in sensitivity over the 6 study years. The statistical calculations were performed using NCSS 2000 statistical software (Number Cruncher Statistical Systems, Kaysville, UT).
The mean age (± standard deviation) of the subjects at recruitment was 29.6 ± 4.6 years (range 15–47). Of 20,465 women, 8595 (42%) were nulliparous, 7777 (38%) had had one and 4093 (20%) two or more deliveries. Ninety-nine percent of the women were white. One hundred two (0.5%) were younger than 18 years, and 164 (0.8%) were aged 40 or more years. Routine karyotyping because of advanced maternal age was offered only to the women aged 40 and older, of whom approximately two thirds were known to have undergone chorionic villus biopsy at 10–11 weeks.
At the first attendance, 13,362 (65%) of the 20,465 pregnancies corresponded to 13–14 completed weeks' gestation by ultrasonography, as originally planned (Table 2). Subjects at less than 11 weeks' gestation by ultrasonography (n = 109; 2%) were given a new appointment, whereas those at 11 or 12 completed weeks (n = 753; 16%) were accepted for the early scan. The mean length of gestation was 13.5 weeks at the early scan.
The screener perceived visualization of the brain, spine (neural tube), and stomach as being inadequate in only 1%–1.5% of cases, whereas four-chamber view of the heart were not seen well in 69%. Because of this inadequate visualization and because the screener midwives had not been trained in early fetal cardiac examination, all the 118 heart defects (including left or right heart hypoplasia) were excluded from the sensitivity calculations.
Of the total of 20,751 fetuses, 307 fetuses (1.5%) had major structural defects (Tables 3 and 4). Of these, 67 fetuses (0.3%) had at least one major structural defect considered detectable by routine ultrasound screening (Table 3). The remaining 240 (Table 4) were not considered to be detectable in our setting and were therefore not included in the sensitivity calculations. The total number of fetuses with anomalies reported to the malformation registry was 1125 (5.5%), but this figure includes minor findings, such as ankyloglossia, luxation of hip, stenosis of lacrimal duct, testis retention, and preauricular tag, which cannot be considered as malformations.
Figure 1 presents the rising sensitivity (learning curve) for identifying the 67 selected major structural defects. Excluding heart defects, the sensitivity for major defects in the first study year 1993 was only 22% (95% CI 2, 60), but it rose progressively to 79% (95% CI 49, 95) in 1998 (P = .009; χ2 test for trend). The sensitivity was 52% (95% CI 40, 65) for the whole 6-year study period. No statistically significant differences were observed among the screeners. Fetuses with increased nuchal translucency were included in these figures in case there was also some structural defect that could be considered detectable by ultrasonography.
The series included a total of 118 fetuses with congenital heart defect. Nine of these were cases of left heart hypoplasia and two were cases of right heart hypoplasia. Among the remaining 107 fetuses with heart defect, there were four with truncus arteriosus, five with transposition of great arteries, eleven with tetralogy of Fallot, six with coarctation of aorta, three with pulmonary stenosis or atresia, eight with atrial-ventricular septal defect, and 28 with atrial and 42 with ventricular septal defects of varying degrees of severity.
In addition to the above-mentioned 118 heart anomalies, there were 122 fetuses with other anomalies, which we did not expect to be detectable in our setting (Table 4). None of these 240 fetuses listed in Table 4 were included in the sensitivity calculations.
Increased nuchal translucency thickness (3 mm or more) was observed in 184 fetuses (0.9%), and all but one underwent karyotyping. Thirty-four (64%; 95% CI 50, 77) of the 53 fetuses with aneuploidy were found. Of the remaining 149 fetuses with normal karyotype, ten (7%) were diagnosed with congenital heart defects; one with left heart hypoplasia, one with right left heart hypoplasia, one with transposition of the great arteries, one with atrial septal defect and pulmonary stenosis, one with coarctation of aorta, two with atrial-ventricular septal defect, and three with ventricular septal defect after birth. Other findings associated with increased nuchal translucency were achondroplasia, pterygium syndrome, thanatophoric dysplasia, cleft lip and cleft palate, Smith-Lemli-Opitz syndrome, Pierre Robin sequence, and a short limb syndrome.
There were only two false-positive cases (ie, fetal anomaly suspected at screening but not confirmed at the tertiary center). One was cystic kidney disease, and the other was suspicion of an encephalocele.
In our study of a large general population, 52% of fetuses with major structural anomalies that we considered detectable by ultrasonography were identified in early screening. This rate is slightly lower than those in a recent Italian report, in which 61% of major anomalies were diagnosed at 14 weeks' gestation.13 In Britain, 59% of major abnormalities were identified at 11–15 weeks.11 We found a low sensitivity during the first year of scanning (only 22%), but it rose to 79% in the last (sixth) year. This kind of learning curve has not been previously described.
Better results obtained by others may be partly attributable to the fact that the examiners were obstetricians dedicated to ultrasonography who used 30 minutes for each scan,12 whereas in our study they were mostly trained midwives, and about 20 minutes were allocated for each scan as part of the routine antenatal care. Thus, the good results obtained by specialists cannot be immediately expected when a screening protocol is implemented in routine obstetric care. However, we found that good results can be achieved with trained midwives, provided there are enough examinations (700 per year for every sonographer) and 3–4 years are allowed for accumulating sufficient experience. The midwives attended quarterly meetings at the University clinic and on-site video and slide training sessions twice a year. The improvement is probably attributable both to increased experience and continuous education.
There are considerable variations in the definitions of malformations between different studies, which renders comparisons of sensitivity difficult, if not impossible. For example, heart anomalies have been included in some studies13 but not in others.14 We intentionally excluded heart defects from the sensitivity calculations, because our midwives were not trained in fetal cardiac examination in early pregnancy. However, we provide the numbers of heart anomalies to allow comparisons with other studies. In particular, setting criteria for clinically significant ventricular septal defect is difficult due to its wide variation in size and severity. The picture is further complicated by the fact that some anomalies, such as cleft lip, are “major” but small in size and hence not easily seen in nontargeted ultrasonography, whereas others are “minor” but easily visible (eg, an ovarian cyst). In addition, it should be clearly stated whether sensitivity is calculated for specific diagnoses made at the time of scanning, or for fetuses identified as just having some signs (such as increased nuchal translucency) suggesting an anomaly, with the final diagnosis being made later in pregnancy or at birth.
Another factor that affects the sensitivity figures is completeness of the data on pregnancy outcome. We had direct access to 95% of the obstetric and pediatric records, and for the remainder, complementary data was available from the national health registers. Our data for sensitivity calculations can thus be regarded as reliable, with only 0.2% of the pregnancy outcomes remaining unknown. Based on a defined population, our results can be assumed to reflect a “true” scenario for screening nonselected pregnancies by specially trained midwives. At least in our setting, screening all low-risk pregnancies by trained obstetricians would be impractical and is beyond the available manpower resources.
During the first study years, we missed several cases with important anomalies, such as abdominal wall defects and anencephaly. The fetus with anencephaly was scanned only transabdominally at 12 weeks' gestation, because the mother declined vaginal scan, which may explain the false negative finding. Skill improved during the years, and all cases with anencephaly, meningomyelocele, and omphalocele were diagnosed in the last 3 study years. The still-rising learning curve in our study suggests a chance for even further improvement. This might be accomplished with more dedication and training, regular auditing, better equipment, and perhaps more than 20 minutes allocated for each scan.
Efforts should be made to improve identification of fetuses with major heart anomalies because they are sometimes associated with an abnormal karyotype and can be life-incompatible or require prompt, high-tech care after birth.
Although the sensitivity for major malformations at the 13–14 weeks' scan already approaches that reported for the midpregnancy scan,16 it cannot replace the midpregnancy scan in diagnosing certain fetal structural defects, such as heart defects. Furthermore, some anomalies, such as hydrocephaly, hydronephrosis, and teratoma often develop after the first trimester and hence cannot be seen at an early scan. On the other hand, most fetuses with chromosomal abnormalities can already be identified during the first trimester by means of increased nuchal translucency2,3 and by absence of the nasal bone.17 Therefore, the early scan and the midpregnancy scan appear to be complementary.
In conclusion, most fetuses with major, noncardiac anomalies can be identified at the end of the first trimester by ultrasonography performed by midwives, provided their systematic training can be arranged and providing a few years' learning curve is allowed.
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