Fetal structural anomalies diagnosed during the first, second and third trimesters of pregnancy using ultrasonography: a retrospective cohort study

ABSTRACT BACKGROUND: The prevalence of congenital abnormalities in general populations is approximately 3-5%. One of the most important applications of obstetric ultrasound is in detection of fetal structural defects. OBJECTIVE: To assess fetal structural anomalies diagnosed using ultrasound in the three trimesters of pregnancy. DESIGN AND SETTING: Retrospective cohort study at the Mário Palmério University Hospital of the University of Uberaba (Universidade de Uberaba, UNIUBE), from March 2014 to December 2016. METHODS: Ultrasound data at gestational weeks 11-13 + 6, 20-24 and 32-36 were recorded to identify fetal anomalies in each trimester and in the postnatal period. The primary outcome measurements were sensitivity, specificity, positive predictive value and negative predictive value for detection of fetal anomalies and their prevalence. RESULTS: The prevalence of anomalies detected using ultrasound was 2.95% in the prenatal period and 7.24% in the postnatal period. The fetal anomalies most frequently diagnosed using ultrasound in the three trimesters were genitourinary tract anomalies, with a prevalence of 27.8%. Cardiac anomalies were diagnosed more often in the postnatal period, accounting for 51.0% of all cases. High specificity, negative predictive value and accuracy of ultrasound were observed in all three trimesters of pregnancy. CONCLUSION: Ultrasound is safe and has utility for detecting fetal anomalies that are associated with high rates of morbidity and mortality. However, the low sensitivity of ultrasound for detecting fetal anomalies in unselected populations limits its utility for providing reassurance to examiners and to pregnant women with normal results.


INTRODUCTION
The prevalence of congenital abnormalities in the general population is approximately 3%-5%. 1 Since the first report of the use of ultrasound in obstetrics, 2 this has become an important tool for detection of fetal structural defects. 3 According to the International Society of Ultrasound in Obstetrics and Gynecology, the ideal period for screening for structural defects is the second trimester of pregnancy (weeks 18 to 22). 4 In Brazil, the preferred period for performing ultrasound screening in the second trimester is between 20 and 24 weeks of gestation. In developed countries, the number of referrals for ultrasound examinations in the first trimester (11-13 + 6 weeks) has increased, while second-trimester ultrasound is considered to be the gold standard for detecting structural anomalies. 5 First-trimester ultrasound has utility for confirming fetal viability and gestational age, evaluating the risk of chromosomal disorders and fetal anomalies and detecting twin pregnancy and chronicity. 4 Evaluation of nuchal translucency in the first trimester has emerged as a tool for screening for fetal structural anomalies. 6,7 There is an association between increased nuchal translucency and chromosomal abnormalities, particularly trisomy 21 and structural anomalies. Greater nuchal translucency has been correlated with increased risk of trisomy 21 and fetal anomalies, especially cardiac abnormalities. 6 More than 80% of fetal anomalies develop before 12 weeks of gestation. Therefore, good visualization of the fetus at this stage enables early detection of structural anomalies. 8 The ultrasound detection rates for major structural anomalies in the first and second trimesters range from 13.0% to 43.6% and from 21% to 85%, respectively. [9][10][11][12] The overall sensitivity increases to 93% when first and second trimester ultrasound examinations are combined. 13 Detection of structural anomalies within the gestational period makes it possible to plan interventions during pregnancy or during the immediate and early postpartum period, thereby reducing perinatal and infant morbidity and mortality. 14,15 In addition, early detection facilitates multidisciplinary planning for maternal-fetal interventions that may be required during the gestational period and provides greater information for parents and relatives. 16

OBJECTIVE
The objective of the present study was to assess the fetal anomalies diagnosed using ultrasound in the first, second and third trimesters of pregnancy. The need for informed consent was waived due to the retrospective nature of the present study.
The ultrasound findings were confirmed during the postnatal period through physical examination of the newborn or imaging examinations, or via necropsy in cases of death. The objective of the present study was to detect structural abnormalities using prenatal ultrasound examination; however, such examinations are unable to confirm syndromic diagnoses.

Participants and anomaly detection
Women with singleton pregnancies in which gestational age had been established using the date of the last menstrual period and was confirmed through ultrasound in the first trimester were included in this study. Cases of major and minor anomalies

Ultrasound examinations
Ultrasound examinations were performed by three experienced examiners with at least five years of experience of using a Voluson In accordance with our department's protocol, second-trimester examinations (20-24 weeks) and third-trimester examinations (32-36 weeks) were offered to all pregnant women after an initial first-trimester ultrasound examination (11-13 + 6 weeks).
The follow-up for fetuses that were found to have structural defects was individualized according to the structural defect identified. The structural anomalies thus detected were divided into eight groups according to the following body systems: central nervous system; face and nape of neck; thorax; heart; gastrointestinal tract; genitourinary tract; skeleton; and others. This last group included anomalies of body systems other than those listed above.

Sample size and statistical analysis
Case recruitment was guided by an expected 3% prevalence of fetal structural anomalies, in a screening cohort with an estimated 50% sensitivity for fetal anomaly detection. We planned to recruit approximately 600 participants in each group, to achieve a sampling error of approximately 4% for sensitivity. Thus, this sample would have 80% power to detect fetal anomalies.
The data were transferred to Excel 2010 spreadsheets (Microsoft Corp., Redmond, WA, USA) and were analyzed using the Statistical Package for the Social Sciences (SPSS) software, version 14.0 (SPSS Inc., Chicago, IL, USA). The following variables were evaluated: maternal age, weight, height, body mass index, number of pregnancies, parity, number of miscarriages, newborn weight, race, history of smoking and alcohol use, history of folic acid use before and during pregnancy, chronic diseases, diseases that started during gestation, history of consanguinity, history of structural abnormalities in previous gestations and/or in the family, type of childbirth and type and location of the structural defect.
Quantitative variables were evaluated using the Kolmogorov-Smirnov test and were presented as means and standard deviations.
Categorical variables were evaluated using absolute and percentage frequencies and were presented in tables. The primary outcome measurements were the sensitivity, specificity, positive predictive value and negative predictive value for detection of fetal anomalies and their prevalence. To perform the calculations, comparison was made between the findings from the ultrasound examination and the clinical and imaging examinations on the neonate after delivery.

RESULTS
A total of 3,377 ultrasound examinations were performed in the prenatal period. A total of 699 examinations were excluded: 44 due to twin pregnancies and 655 because the delivery did not take place in our service and/or the patient was lost to follow-up.
Thus, a total of 2,678 examinations were included in the present statistical analysis. These were divided into three groups, performed at 11-13 + 6 weeks (n = 1,102), 20-24 weeks (n = 683) and 32-36 weeks (n = 893) (Figure 1). After application of our inclusion and exclusion criteria, it was found that only 18.6% (498/2,678) of these women underwent ultrasound examination in all three trimesters. The percentages of the women who underwent ultrasound examination in the first trimester alone, second trimester alone and third trimester alone were: 17 Table 5).

DISCUSSION
The present study evaluated the fetal structural abnormalities in an unselected population, using prenatal ultrasound in the first, second and third trimesters of pregnancy. The international classification of diseases of the World Health Organization aims to classify these structural defects according to etiology or pathogenetic mechanism. 19 However, in the present study, structural abnormalities were classified according to the body systems in which they occurred, in order to determine the systems that were most frequently affected in an unselected population.
The prevalence of structural defects was 2.95% during the prenatal period and 7.24% during the postnatal period. Oakley et al. 1 reported that the prevalence of fetal anomalies at birth ranged from 2% to 5% in general populations. In the United States and Europe, the rates of fetal anomalies at birth have been reported to be 3.0% and 2.4%, respectively. 20,21 In Saudi Arabia, the prevalence of fetal anomalies at birth was reported to be 4.6%. 22 The primary factors that affect the prevalence of fetal anomalies in different populations are consanguinity, use of assisted reproduction techniques, tobacco exposure, air pollution, water contamination and pesticide and agrochemical exposure. [23][24][25][26][27][28] The rates of consanguinity and smoking described in Brazilian populations have been lower than those in other countries. 22,29 We postulate that the higher prevalence of structural defects observed in the present study (higher than observed in North America, Europe and Saudi Arabia) may have arisen through assessment of cases referred to a tertiary-level healthcare center, instead of cases within a general population.
The prevalences of structural abnormality types vary according to the population assessed and the time of diagnosis. Molina-Giraldo et al. 30 conducted a study in Bogota, Colombia, and found that the most common fetal anomalies at birth were those of the central nervous system. Sallout et al. 22 reported that genitourinary tract anomalies were the most frequently diagnosed fetal anomalies during the prenatal period and at birth in Saudi Arabia. In the present study, genitourinary tract and cardiac anomalies were the most frequently diagnosed anomalies during the prenatal period and at birth, respectively.
The rate of detection of fetal cardiac defects has been reported to be low and dependent on the study population. 31,32 The sensitivity of fetal echocardiography for diagnosing cardiac anomalies was found to be 33.9% in low-risk populations and 68.8% in highrisk populations, 31 with septal defects accounting for the majority of cases of diagnostic failure. 32 The high frequency of genitourinary tract anomalies observed in the present study may have been due to their greater ease of detection through ultrasound, in comparison with defects of other body systems such as the heart and central nervous system.
During the first trimester of pregnancy, the sensitivity of ultrasound for detecting fetal anomalies in the present study ranged 3) 0 (0) Craniotabes/asymmetric skull 0 (0) 0 (0) 0 (0) 0 (0) 6 (3.1) Face and nape of neck 2 (14.2) 0 (0) 4 (11.2) 6 (7.6) 17 (8.8)  from 13.0% to 43.6%. The detection rate was much higher when a detailed morphological protocol was adopted, such that up to 76.3% of major structural defects were detected. A previous study in a general population reported a first-trimester detection rate of 90% for complex congenital heart disease (either alone or in association with extracardiac abnormalities) and 69.5% for complex central nervous system anomalies. 33 The sensitivity of ultrasound has been found to be higher in the second trimester, ranging from 21% to 85%. [9][10][11][12] Detection of fetal anomalies in the third trimester is technically more challenging due to fetal growth, poor imaging with static  ultrasound and decreased quantities of amniotic fluid. 34 To date, few studies have evaluated the sensitivity of ultrasound for diagnosing fetal anomalies in the third trimester. 34,35 However, this examination has an important role in identifying defects, particularly those of the central nervous system and genitourinary tract that do not develop or become evident before the third trimester. 36,37 Manegold et al. 34  These defects are often small and/or transitory. 39 Chitty et al. 39 indicated that only clinically significant cardiac defects should be included when assessing the ability of ultrasound to detect structural defects. Despite this recommendation, simple cardiac defects and other defects such as congenital dislocation of the knee and ogival palate were present in the present study to evaluate the limitations of ultrasound for diagnosing fetal anomalies.
The specificity, negative predictive value and accuracy of ultrasound for identifying fetal structural anomalies were high in all three trimesters of pregnancy, despite low sensitivity and positive predictive value values. These results demonstrate that ultrasound is a reliable method for confirming structural defects and for reassuring examiners and pregnant women with normal results. The low positive predictive value may be explained by the low prevalence of fetal anomalies in the present study sample.
The limitations of the present study were its exclusion of a large number of cases due to loss of follow-up and lack of postnatal results, its small number of cases with fetal anomalies and its retrospective nature. It was not possible to determine the cumulative accuracy of ultrasound, since not all the cases included had a first-trimester scan. Furthermore, first-trimester scans have not been established as routine by the Brazilian Ministry of Health. 40 We carefully excluded from the analysis all fetal anomalies that were repeatedly reported in subsequent scans, in order to avoid inconsistencies in the accuracy of the first, second and third trimester scans.
The strength of the present study was its inclusion of an unselected population in a single center, which resulted in a high follow-up rate during pregnancy.

CONCLUSION
In summary, ultrasound is a reliable tool for counseling the parents of children with severe fetal anomalies that are associated with high rates of morbidity and mortality. However, the low sensitivity of ultrasound in detecting fetal anomalies in unselected populations limits its utility for providing reassurance to examiners and pregnant women with normal results. Table 5. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy of ultrasound in the first, second and third trimesters of pregnancy