| 1Background and Subject sourcesFirst trimester (11to13+6weeks) ultrasound was appeared in the early1990s, which was initially used to screening21-trisomy, and then extended to screening13-trisomy and18-trisomy. As the equipment and technique improving, trained sonographer can detect more than80%of fetal anomalies. The vast majority of fetal anomalies diagnosis become early due to11-13+6weeks preganancy routing ultrasound, reducing the impact of induction of labor for pregnant women physiological and psychological, especially in some foreign countries, to avoid the gestational age of induction of labor by the ethical implications of constraints, so in early pregnancy ultrasound screening becomes an important direction of the prenatal ultrasound. The greater detail of the fetal anatomy including limbs in the first trimester had been described by sonography in1980s, and the gestation age for consistent detection also had been demonstrated. Many limb abnormalities are detectable in the first trimester, however, given most of them are reported in case reports or retrospective researches, the potential value of a first-trimester ultrasound scan for fetal limbs in particular warrants further investigation.Shenzhen Maternity&Child Healthcare Hospital developed ultrasound screening fetal malformations in early pregnancy (11to13+6weeks’) in2005,and establish detailed guildline for ultrasound examination in this period, including screening for aneuploid in early pregnancy(fetal NT, nasal bone, ductus venosus), brain, facial, heart, limbs, abdominal wall et al. The purpose of our sduty was to diagnosing fetal major malformations in the first trimester. In the context, we took part in the research on a part of the National Key Technology R&D Program in the11th Five year Plan of topics’Study on new technique of prenatal ultrasound screening and diagnosis’(Number:2006BAI05A04) of China.2Objective and significanceTo assess the feasibility and potential value of a first-trimester ultrasound scan in detecting fetal limb malformations by transabdominal, and summarize the ultrasonographic features of fetal facial malformations to provide reliable technical standards and ultrasonic guildline in screening limbs structure in an early pregnancy.3Data and methods3.1Data:In a period from October2008to the end of January2011, women scheduled their first-trimester ultrasound screening for aneuploidy to our Prenatal Diagnosis Center at Shenzhen Maternity and Child Healthcare Hospital between11-13+6weeks, were invited to participate in this prospective study.. The couples are local residents. Singleton or twin pregnancies. Patients were recruited consecutively, including parent information and personal medical history, current pregnancy records and reproductive history. This study was approved by the Institutional Review Board of the Shenzhen Maternity&Child Healthcare Hospital, which is an affiliation of the Southern Medical University, China. Ultrasound results in early pregnancy of each enrolled fetus were compared with mid-trimester ultrasound results or after birth. The fetus of severe deformities and facial malformation who were diagnosised by ultrasound, informing the parents of fetal outcome, then the parents decide whether to continue pregnancy. With the consent of the pregnant women, we conducted post-natal ultrasound and pathological examination for labored fetuses. Date were collected regarding second-trimester sonographic findings, fetal limb malformations, earliest gestation of diagnosis, associated structure abnormalities, karyotypes, autopsy results, perinatal outcomes., Subsequent follow up were obtained from the neonatal birth defect databases, electron medical records or telephone patient enquiry3.2The first trimester sonography strictly followed the guidelines established by The Fetal Medicine Foundation, UK, and was approved by our Institutional Review Board. Certified doctors who have more than five years experiences of fetal sonography performed the ultrasound examination. Briefly, All the fetus were examined by transabdominal on high resolution ultrasound machines:Acuson Sequoia512, Antares and S2000(Siemens Medical Solutions, Mountain View, CA, USA) using4.0～6.0MHz curvilinear transducer. In addition, evaluation of the fetal anatomy for gross fetal anomalies is also performed as recommended by The Fetal Medicine Foundation. Assessment of the contents of the brain, face, chest, stomach, bladder, liver, umbilical artery, heart and upper limbs, lower limbs and so on.The examiner checked the measured data and assess the contents of fill in a form.3.2.1Measurement of nuchal translucency:The ability to achieve a reliable measurement of NT is dependent on appropriate training and adherence to a standard technique in order to achieve uniformity of results among different operators.The optimal gestational age for measurement of fetal NT is11weeks to13weeks and6days.(1) The minimum fetal crown-rump length should be45mm and the maximum84mm.In the assessment of fetal NT the ultrasound machine should be of high resolution with a video-loop function and callipers that provide measurements to one decimal point.(2) Only the fetal head and upper thorax should be included in the image for measurement of NT.(3) The magnification should be as large as possible and always such that each slight movement of the callipers produces only a0.1mm change in the measurement. In magnifying the image, either pre or post freeze zoom, it is important to turn the gain down.(4) The maximum thickness of the subcutaneous translucency between the skin and the soft tissue overlying the cervical spine should be measured. The callipers should be placed on the lines that define the NT thickness-the crossbar of the calliper should be such that it is hardly visible as it merges with the white line of the border and not in the nuchal fluid.(5) During the scan, more than one measurement must be taken and the maximum one should be recorded.(6) Care must be taken to identified the meningocele in the neck.(7) The umbilical cord may be round the fetal neck in5-10%of cases and this finding may produce a falsely increased NT. In such cases, the measurements of NT above and below the cord are different and, in the calculation of risk, it is more appropriate to use the average of the two measurements.(8) Care must be taken to distinguish between fetal skin and amnion because, at this gestation, both structures appear as thin membranes.3.2.2Measurement of fetal crown-rump length:fetal crown-rump length should be measure at the mid-sagittal section of the fetus in a natural position, showing nasal bone and extend genital organ.the largest distance should be measured from cranial roof to hip.but limbs and yolk sac could not be included. Three measurements must be taken and the mean one should be recorded.3.2.3Fetal ductus vensus were measured according to the following criteria:the examinations were undertaken during fetal quiescence, the magnification of the image was such that the fetal thorax and abdomen occupied the whole screen,a right ventral mid-sagittal view of the fetal trunk was obtained and color flow mapping was used to demonstrate the umbilical vein,ductus venosus and fetal heart. The pulsed Doppler sample was small (0.5-1.0mm) to avoid contamination from the adjacent veins and it was placed in the yellowish aliasing area which is portion immediately above the umbilical sinus.3.2.4S Fetal limbs in early pregnancy were scanned using a sequence approach: displaying upper arm and humerus, forearms, radius and ulna, hands in proximal to distal direction. The thigh and femur, crus and tibia, fibula, feet was attempted from the sagittal section of each structure. The position and movement also should be observed during the scan. The fingers and toes were not requested to calculate. The fetus spontaneously assumes positions of limbs allow to visualize the structures easily in11to13weeks. Rest for about15-20minutes would be required if the examination was obstructed due to the fetal position or uterine contraction at first. Failed evaluation of the fetal limbs would be considered until for several times. The consistent detection of fetal limbs is dependent on appropriate training, efforts also must be focused on the maintenance of an image quality control every month.All images were stored in machines and workstations, and were analyzed by the other two doctors off-line, assessment of the sections to observe the anatomical structure, to the views of the two doctors agreed to a unified standard, when the divided views, the third doctor to assess.3.3Statistical methods:Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS13.0) and the scatter diagram used to define increased NT was calculated from5269normal singletons. Measurement data were expressed as mean±standard deviation, count data were expressed as rate.4Result4.1General conditionFrom October2008to January2011, a total of8310sequential women were examined in the first trimester and complete pregnancy outcomes were achieved in68.1%(5663/8310). Of these,237women accepted for the early scan whose menstrual age was in11to14weeks but fetus CRL outside the range45-84mm were also included into our study. A total of5663(including174twin pregnancies) women were recruited into our study.5569fetuses, including5187normal and212abnormal singletons,154normal and16abnormal twin pregnancy, were classified into three groups by gestational age or CRL:571(10.1%) cases were between11-11+6weeks (CRL:45-52mm),2690(47.5%) cases between12-12+6weeks (CRL:52-66mm),2402(42.4%) cases between13-13+6weeks(CRL:66-84mm). The mean maternal age was29.8years (range17.5-47.5years; SD4.2). The mean gestation age was12.8weeks (range10.1-14.8weeks; SD0.7).A11the major structures of limbs were visualized by transabdominal at the first trimester scan since almost all the pregnant women refused to take the transvaginal sonography.The incidence of fetal limb malformations was0.493%(41/8310) in our series. The detection rate of fetal limb abnormalities in the first trimester was73.2%(30/41), and when the first and second trimester scans combined the detection rate increased to85.4%(35/41). It implied that85.7%(30/35) of limb abnormalities that once diagnosed in the second trimester now can be brought forward to the first trimester. Limb reduction defect was the most common seen in the first-trimester with a frequency of15, followed by club foot (6cases), lethal skeletal dysplasia(3cases), sirenomelia(3cases), malposition(2cases) and left limbs dysplasia(lcase). During the second trimester scan we identified5cases of limb abnormalities(two Split hands and two club feet, one Syndacty). We also found6fetus had a limb abnormality postnatally including one club foot, one syndactyly, two polydactyly, and two fifth-finger camptodactyly. Moreover, polysyndactyly was an additional perinatal finding when the diagnosis of bilateral absent of fibula had been established in the first trimester.Most of major limb malformations can be detected by sonographers in the first trimester (table1). Limb reduction defect, lethal skeletal dysplasia, sirenomelia were always detectable in our series. And club foot achieved a high detection rate of67%(6/9) in the first trimester scan. But the split hand, Syndacty, Polydacty, Camptodactyly are manifested only in the second trimester or even postnatally, and are therefore difficult to detect at11-13weeks.4.2The potential value of a routine first-trimester ultrasound scan in detecting fetal limb malformationsThe sensitivity, specificity, positive and negative predictive of first trimest scaning of fetal limbs were73.2%,100%,100%and99.8%respectively.4.3The detection rate of the limbs structures in the first trimest533fetus scaned by three docters were chosed randomly for analyzing, the mean time of scaning the limbs is98.6±37.4s(rang:36s-189s). In our study, transabdominal ultrasound could visualiazing100%of the major structures of limbs including the upper arm and humerus, forearms,radius and ulna, hands and fingers, the thigh and femur, crus and tibio and fibula, two feet.4.4Increased nuchal translucency associated with limb abnormalitiesThe NT and CRL measurements were obtained in39cases of limb abnormalities and failed on two cases of body stalk anomaly for their fixed postures.74.2%(23/31) of limb abnormalities associated with other structure or chromosome abnormalities had a NT greater than or equal to the95th centile (Figure1), nevertheless all the Isolated limb abnormalities (8cases) were related to a normal NT. Significantly increased NT was observed in all cases(3/3) of lethal skeletal dysplasia, and in78%(7/9) of club feet,80%(8/10) of body stalk anomaly,67%(2/3) of sirenomelia in our series. Two cases of absent radii and club hand with edema and/or cardiac abnormality may result in an increased NT, but the one without other abnormalities was present with a normal NT. Additionally, the phocomelia with an increased NT of2.9mm was also reported.4.4Limbs malformation in the first trimester4.4.1Club foot:Of the9cases with club foot, we were able to identify6in the first trimester. In the two cases diagnosed in later ultrasound, one had trisomy18related to FGR and fetal edema, and another had complete transposition of the great arteries with a significantly small cerebellum.In our series the rate of club feet identified was67%in the first trimester,89%in the second trimester, and the other fetus was normal through repeated ultrasound examination and presented as having a club-foot at birth was considered as a later development club foot.4.4.2Limbs deficiencyLimbs deficiency was identified in15cases, including9cases of transvers Limbs deficiency and6cases of Longitudinal deficency. We also recognised an right leg phocomelia related to megalocystis and absent A-wave with an normal NT. Limb abnormalities associated with other structure or chromosome abnormalities had a NT greater than or equal to the95th centile, while all the Isolated limb abnormalities (3cases) were related to a normal NT. 4.3.3Congenital deformity of hand8cases of congenital deformity of hand were noticed. But only one syndactyly (12.5%) were diagnosed in the first trimester. One syndactyly, two polydactyly, and two fifth-finger camptodactyly were identified postnatally. And polysyndactyly was an additional perinatal findings when the bilater absent of absent fibula had been established in the first trimester. Two split hand were identified during the second trimester.4.3.4Sirenomelia was a rare and lethal congenital anomaly, although exceptional cases without renal agenesis may survive. Oligoamnios in later second trimester usually makes the diagnosis difficult, whereas first trimester diagnosis of sirenomelia has been illustrated. We demonstrated that reliably diagnosis of sirenomelia can be achieved with a fused lower extremity were identified in our first trimester scan. Power color Doppler confirmed the diagnosis in three cases with a great intraabdominal vessel directly continued in the umbilical cord. After informing of the poor prognosis, all parents opted for a termination of the pregnancy to prevent considerable psychological traumas of the family after late diagnosis. However, only one took the ultrasonography on corpse.4.3.5Lethal skeletal dysplasiaIn the present cases, it was impossible to confirm the final diagnosis for lack of autopsy and extended analysis.But following features assisted in considering a potential diagnosis of skeletal dysplasia in the first trimester, for instance, obviously short and/or bowed long bones (3in3cases), fractures of femurs (1in3cases), poor ossification of all bones(1in3cases), narrow thorax (1in3cases). Thus there is no doubt about that it is necessary to perform a first-trimester limbs evaluation. However, It worth to mention that even if a meticulous survey of the fetal limbs couldn’t exclude all skeletal dysplasia in an early pregnancy as the increased NT present as the only early sign.4.3.6Abdominal wall defectsLimb-body wall complex, alternatively known as "body stalk anomaly", is a severe congenital anomaly with uniformly dismal prognosis, therefore an early diagnosis of body stalk anomaly is optimal to prevent more harm. It has been reported in a well-documented series and proved a high prevalence increased from approximately1/7500to1/1738in the first trimester. We provided a incidence of12/5663, account for38.7%(12/31) limbs abnormalities identified in the first trimester scan. Although the fetal karyotype is usually normal in this condition, the increased NT was observed in71.4%of the cases. In our series the percentage was70%(7/10) excluding2cases that the measurements were failed.4.3.7Limb abnormalities associated with other structure or chromosome abnormalities, syndromes.80.5%(33/41) limbs abnormalities associated with other structure or chromosome abnormalities. Only10patients took the karyotype analysis, one trisomy18and one trisomy21were identified. And a fetus with long Y chromosome developed fetal growth restriction(FGR), micromaxillary deformity, hypospadias with penoscrotal transposition, the fifth-finger camptodactyly.5ConclusionOur study was firstly proposed using a systematic continuous sequence approach to screen fetal limb malformations in the world. The displaying rate of limbs structures were about100%, which was completely unaffected by gestational age.The incidence of fetal limbs malformations was0.493%(41/8310) in the first-trimester approximate the incidence of0.57%reported at12～16weeks by Bronshtein. We demonstrated that73.2%(30/41) limbs defects could be identified by the11-13+6weeks scan. Compare with the second trimester scan, the first trimester scan can identified85.7%(30/35) of limb abnormalities. The sensitivity, specificity, positive and negative predictive of first trimest scaning of fetal limbs were73.2%,100%,100%and99.8%respectively.The main arm of this study was to recognize the major limbs abnormalities rather than the minor ones, and proved that most of major limb abnormalities such as limb reduction defect, lethal skeletal dysplasia, sirenomelia are reliable detected in the first trimester through our study. Nevertheless, the detection of abnormal digitals was relatively low. Significantly increased incidence of NT above the95th percentile was observed in cases of abdominal wall defects and lethal skeletal dysplasia in our series. Nevertheless our data emphasized that there is no deducible connection between the increased NT and isolated limb abnormalities, but significantly increased incidence of NT above the95th percentile was observed in cases of limb abnormalities associated with other structure or chromosome abnormalities. |
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