Background

Diagnosis of congenital abnormalities has become very important in reducing the incidence of perinatal mortality since medical advances have led to a decrease in conditions like infections and starvation [1].

Twenty to twenty-five percent of perinatal deaths are caused by congenital deformities. Presently, numerous hereditary and other medical conditions can be diagnosed early in pregnancy. Prenatal diagnosis uses different noninvasive procedures to determine any abnormality in newborn baby [2].

Ultrasound is the preferred non-invasive screening method for the diagnosis of congenital abnormalities due to its reliability, affordability, and sensitivity of detection. More congenital defects are being found antenatally than in the past due to more advanced diagnostic tools. All pregnant women should have routine prenatal ultrasound examinations to look for these anomalies. When congenital anomalies are detected early in pregnancy, mothers are better prepared to make informed decisions about their pregnancy and, if necessary, seek fetal intervention. This improves perinatal and long-term outcomes [3]. Prenatal screening can lower the birth rate of deformed fetuses, improving the quality of newborns and improving the growth of each family and society as a whole [4].

Two-dimensional ultrasound (2D-US) has been taken over as the primary and standard method for prenatal screening [5]. 3D/4D US offers multiplanar view, tomographic view, surface view, transparent view, and volume contrast imaging that are not available in conventional (2D) US, and provide a precise illustration of the normal and abnormal anatomy of the fetus by reloading volumes and browsing through them without the patient present, digital storage of volumes makes it possible for virtual exams [6, 7].

The primary goal of this study was to compare the roles of 2D-US and 4D-US in diagnosis of prenatal fetal non-cardiac congenital abnormalities, as well as the accuracy of their combined and individual diagnoses. Additionally, we assessed the risk factors for congenital defects in fetuses with abnormal development, which is essential to improving the newborn population's quality.

Methods

The current prospective study was conducted between January 2022 and January 2023 at the radiodiagnosis and medical imaging department of our university hospital. There were 100 pregnant women with high-risk pregnancies whose ages ranged between 18 and 45 years (mean age + SD = 29.03 ± 2.71), and the mean gestational age was 27.90 + 0.72 weeks, with the gestational weeks ranging from 24 to 34 weeks. In terms of parturient types, there were 57 multiparas and 43 primiparas. Inclusion criteria: high-risk pregnancy, including diabetes, pre-eclampsia, and other systemic diseases that affect pregnancy like epilepsy, thyroid disease, heart or blood disorders, poorly controlled asthma, infections, and women with bad obstetric history consanguineous marriage, prior history of fetal malformation; positive family history of fetal anomalies, and in vitro fertilization. Exclusion criteria: normal fetal biometry and pregnant women after 34 weeks. The study was approved by our university's ethical committee. All patients signed an informed consent form. And detailed medical, obstetric, past, and family histories were obtained.

A total of 100 pregnant women were examined by using Toshiba Aplio 500 ultrasound equipment with a convex abdominal probe (frequency of 3–5 MHz) and a 4D trans-abdominal probe.

Ultrasound examination

The 2D and 4D U/S examinations were done by three sonographers with at least 5 years' experience in fetal U/S, and the results were taken by consensus.

2D ultrasound examination

All patients underwent a 2D-US examination while lying on their backs with their abdomens exposed, and the fetus's various features were carefully examined. The biparietal diameter (BPD), head circumference (HC), femur and humerus lengths, abdominal circumference (AC), placenta location and grade of development, amniotic fluid index, and vertical maximum pocket depth were examined as biological markers of the fetus. The fetal face was examined in multiple planes; The lips and palate were seen in multiple planes; and the continuity of the spine was examined. The growth of the heart and lungs, among other chest organs, and abdominal organs such as the stomach, bowels, kidneys, and urinary bladder (Fig. 1).

Fig. 1
figure 1

A pregnant female aged 28 years primigravida presented at 24 weeks of gestation and was diabetic. She had a history of medication during pregnancy with a positive history of consanguinity without any prior antenatal checkup. A 2D US axial and coronal images of the fetal head revealed an absent cranium; the eyes are pronounced, giving a typical froglike appearance (blue arrow). B Reconstructed 4D US image of fetal head with absent cranium and rudimentary brain, giving a frog-like appearance to the fetal face (blue arrow). C Increase amniotic fluid (polyhydramnios (AFI = 29)). D Post-termination image confirming the diagnosis of anencephaly

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4D ultrasound examination

To guarantee the clarity of the picture capture, the fetus' dynamic imaging was shown. The examined organ, especially the face, must be surrounded by an adequate amount of amniotic fluid to take good images. 4D examination time was 15 to 20 min (Fig. 2).

Fig. 2
figure 2

A pregnant female aged 38 years, multigravida, presented at 25 weeks of gestation. She had a history of medication during pregnancy and a family history of previous congenital anomalies that referred her for an anomaly scan. A A 2D US axial image of the fetal abdomen with a minor abdominal wall defect measures 2.2 cm, passing a sac containing part of the liver and some bowel loops with an overlying membrane covering the content. B Color Doppler image showing insertion of the umbilical cord into the sac. C, D 4D US images showing herniation of abdominal content through the abdominal wall defect (arrow). E Postnatal image confirming the diagnosis of omphalocele

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4D protocol

The following steps were used to capture a 4D picture of each fetus part: (1) Press the 4D button to begin the examination. (2) Establishing and adjusting the ROI, the 4D volume box was set to contain the whole region of interest (ROI); (3) Changing the flexible cut line and positioning the volume box's cut line in the amniotic fluid, (4) By pushing the 4D button, the volume was captured in the axial view (Fig. 3).

Fig. 3
figure 3

A pregnant female aged 20 years, primigravida, presented with 24 weeks of gestation, was hypertensive, and had a positive history of consanguinity. She had a previous US examination that revealed abnormal measurements. Referred for an anomaly scan. A 2D US axial and longitudinal images showing shortening of the length of the femur and humerus (aged about 16 weeks) in comparison to head and abdominal circumference and amenorrhea (about 24 weeks). B Small chest in comparison to abdomen shown in axial sections of the chest and abdomen. C 2D US sagittal image of the chest and abdomen showing a narrow chest. D A 4D US surface rendering image of a hand showing a small hand with the 2nd, 3rd, and 4th fingers appearing separated and similar in length (trident hand). E 4D US revealed shortening of the proximal bones of the upper and lower limbs (rhizomelia) and a protruding forehead (frontal bossing) with a depressed nasal bridge. A case of skeletal dysplasia (Achondroplasia rhizomelia) confirmed by genetic testing

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The organ was next examined in the three orthogonal planes (sagittal, axial, and coronal) using the multiplanar mode. Additionally, Multiview mode was used, which presented up to 16 planes of a volume simultaneously and was similar to CT or MRI scans with multilevel slices every 1 mm or fewer. The facial structures, including the eyes, nose, lips, ears, and limbs, were examined using the 4D surface rendering method. In order to assess the fetus' skeletal structure, 4D maximal mode was applied. Adjusting the image through the use of options like panning, zooming, rotating, and removing the 4D image's undesirable area (Fig. 4).

Fig. 4
figure 4

A pregnant female aged 22 years, multigravida, presented with 26 ± 2 weeks of gestation, was hypertensive, presented with eclampsia, had a positive history of consanguinity, and had a past history of a fetus with facial anomalies. She had one previous US examination that revealed polyhydramnios and referred her for an anomaly scan. A, B 2D US coronal images of the fetal face showed a loss of integrity of the upper lip. C 2D US showed an increase in amniotic fluid (polyhydramnios). D Doppler examination revealed an increase in the resistive index of the umbilical artery (RI = 0.76) with low diastolic flow. E A surface-rendering 4D US image of the fetal face revealed loss of integrity of the upper lip, confirming the diagnosis of cleft lip. A case of paramedian cleft lip was confirmed postnatally

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Interpretation and outcome measures

The accuracy, sensitivity, and specificity of 2D-US and 4D-US as well as their combined examinations in the detection of fetal abnormalities were established by postnatal follow-up on all patients. Postnatal findings and the abnormality diagnosed by an obstetrician were considered the gold standard for the accuracy of 2D and 4D US results (Fig. 5).

Fig. 5
figure 5

A pregnant female aged 40 years with multigravida presented at 27 weeks of gestation, was hypertensive, and had a past history of babies with congenital anomalies. Without any previous ultrasonographic examination. A, B 2D US images of the fetal leg in the longitudinal plane revealed the tibia, fibula, and foot were seen in the same plane, and the foot appeared medially deviated; this abnormal positioning persists during the duration of the scan. C, D Surface rendering 4D US images of the fetal foot showed a medially deviated planter-flexed foot. Case of unilateral talipes equinovarus (clubfoot) confirmed postnatal

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Statistical analysis

The data were fed to the computer and analyzed using IBM SPSS software package version 20.0. (Armonk, NY: IBM Corp.) Qualitative data were described using numbers and percents. The Kolmogorov–Smirnov test was used to verify the normality of the distribution. Quantitative data were described using range means and standard deviations. The significance of the obtained results was judged at the 5% level. The Chi-square test was used for categorical variables to compare between different groups, and Fisher’s Exact was used for correction for the chi-square when more than 20% of the cells had an expected count less than 5. Accuracy: rate of agreement = (true positives + true negatives)/total tested × 100%. Sensitivity: Positivity in diseased patients = true positives/true positives + false negatives × 100%. Specificity: Negativity in non-diseased patients = true negatives/true negatives + false positives × 100% (Fig. 6).

Fig. 6
figure 6

A pregnant female aged 31 years presented at 28 weeks of gestation with a positive history of consanguinity and a past history of babies with skeletal congenital anomalies without any prior antenatal checkup. A A 2D US scan of a transverse section of the fetal foot (planter view) showed that the second and third toes were fused together, as well as the presence of an extra digit lateral to the little toe. B Six digits were also seen in sagittal view. C, D 2D US axial and coronal images of the fetal abdomen showed marked ballooning dilatation of the left renal pelvis with slight fullness of the renal pelvis on the right side. E, F Surface rendering 4D US image of the fetal foot confirming the fusion between the second and third toes and the presence of six digits A case of syndactyly and postaxial polydactyly associated with hydronephrosis (PUJO) was confirmed postnatally

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Results

This study was carried out on 100 pregnant women with high risk pregnancy who expected to give birth to deformed newborn babies. Among the 100 pregnant women with high-risk pregnancy, there were 75 cases who had normal fetus and 25 cases had fetuses with non-cardiac congenital anomalies, including 6 cases (24%) of neurological malformations, 4 cases (16%) of abdominal malformations, 4 cases (16%) of genitourinary system malformations, 4 cases (16%) of skeletal system deformities, 3 cases (12%) of facial deformities, 2 cases (8%) thoracic malformation, and 2 cases (8%) hydrops fetalis (Table 1).

Table 1 The prevalence of fetal malformations (N = 100)
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Analysis of risk factors for fetal malformation showed that consanguinity, past history or family history of congenital malformation, history of medication during pregnancy and diabetes were related to fetal malformations, and the differences were statically significant (P < 0.05), while increased age of mother > 35 and hypertension during pregnancy were statically insignificant (P > 0.05) (Table 2).

Table 2 The significance of maternal risk factors for fetal malformation
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Out of 25 cases confirmed postnatal to have fetus with non-cardiac congenital malformation, 2D US established the diagnosis of 19 (76%) malformation, whereas 4D US diagnosed 20 (80%) malformation, whereas combined 2D and 4D US diagnosed 22 (88%) So the combined diagnosis of 2D-US + 4D-US achieved obviously higher diagnostic value (Table 3).

Table 3 Classification of fetal malformation by 2D, 4D, and combined examinations, with correlation with postnatal outcomes (N = 25)
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Regarding the comparison of 2D-US, 4D-US for the diagnosis of fetal malformations other than cardiac. The results of the comparison between various inspection techniques and the gold standard were exactly consistent with the incidence of neonatal malformations following delivery (Table 4).

Table 4 Correlation of pregnancy's outcomes with 2D and 4D ultrasounds and combined examination
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The accuracy, sensitivity, and specificity of the 2D-US diagnosis were 84%, 76%, and 86.67%, respectively, whereas the accuracy, sensitivity, and specificity of the 4D-US diagnosis were 87%, 80%, and 83.33%, respectively. The accuracy, sensitivity, and specificity of the combined 2D-US and 4D-US diagnosis were 94%, 88%, and 96%, respectively (Table 5).

Table 5 The efficiency of various ultrasonic detection techniques in the diagnosis of fetal malformation
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Discussion

The results of this study showed that 25 non-cardiac fetal malformations proven postnatally were detected among the 100 pregnant women with high-risk pregnancies including diabetic, pre-eclampsia, other systemic diseases that affect pregnancy like epilepsy, thyroid disease, heart or blood disorders, poorly controlled asthma, infections, and women with bad obstetric history such as when a woman has previously had problems in previous pregnancies. This may include miscarriage, stillbirth, intrauterine fetal deaths, intrauterine growth retardation and congenital anomalies. The accuracy, sensitivity, and specificity of the combined 2D-US and 4D-US diagnosis were clearly greater than those of each method used alone.

Several studies have been conducted to compare the accuracy, sensitivity and specificity of different ultrasound methods. In a study by Yu et al. [8]. In terms of accuracy, sensitivity, and specificity, 2D-US diagnosis scored 81.40%, 43.68%, and 82.92%, whereas 4D-US scored 83.67%, 51.72%, and 84.95%, and 2D-US plus 4D-US scored 93.59%, 90.80%, and 93.70%. It shows that the 2D-US + 4D-US combination diagnosis had noticeably superior accuracy, sensitivity, and specificity to either 2D-US or 4D-US. Also Deng et al. found inferior diagnostic accuracy of 2D-US to 2D-US plus 4D-US for fetal anomaly at gestational week [9].

According to one study by Goncalves et al. [10] examined 99 fetuses (54 were normal and 45 had 82 malformations) and observed conformity between 2 and 3D/4D ultrasonography for 90.4% of the findings. The sensitivity [92.2% vs 96.1%] and specificity [76.4% vs 72.7%] of 3D/4D and 2D US, respectively, were insignificantly different (P = 0.223) in detection of congenital malformations confirmed postnatally.

Our study also analyzed the risk factors leading to fetal malformations. The results showed that consanguinity, increased maternal age, past history or family history of congenital anomalies, history of medication during pregnancy and maternal diabetes were all risk factors for fetal malformations. Consanguinity plays an important role in the occurrence of congenital malformations, This finding is in consistent with the study by Sarkar et al. [11] who found that (40%) of consanguineous couples had some congenital malformation in their babies which was highly significant, whereas in non-consanguineous couples, the prevalence was only 2.2%.

As regards to past history and family history of congenital anomalies, in this study 5 cases out of 25 cases (20%) had positive past history of birth defects or similar congenital malformation in some members of the family. This finding consistent with El Koumi et al. [12] who stated that a family history of birth defects has been associated with an increased recurrence risk of congenital anomalies, with a recurrence rate ranging between 2 and 5%.

As regards to increased maternal age and babies born with congenital anomalies. This study revealed that a majority of malformed babies were born of mothers aged 25–35 years; though, it was statistically insignificant. This finding consistent with those of Yu et al. [8] found that maternal age ≥35 was independent risk factors for fetal malformations. Also Sarkar et al. [11] who found that most of malformed babies were born of mothers aged 20–29 years; though, it was statistically insignificant, on the other hand, Chen et al. [13] found that teenage pregnancy was significantly associated with increased risk of congenital anomalies specially CNS anomalies.

As regard history of medication during pregnancy, in the current study 13 cases out of 25 cases (52%) have history of taking medication during pregnancy for different diseases. This finding is in consistent with the study by Martha et al. [14] who found that the anti-epileptic drugs exposure in early gestation increase the risk of birth defects associations with valproic acid exposure were appearing to increase the risk of neural tube defects, oral clefts and hypospadias. And Yu et al. [8] found that the history of medication during pregnancy is major risk for development of fetal malformations.. On the other hand BT Bateman et al. [15] found that maternal use of β-blockers in the first trimester is not associated with a large increase in the risk for overall malformations.

As regard to diabetes, the current study showed that incidence of fetal anomalies increases with pre-existing diabetes and gestational diabetes. This finding is in consistent with the study by Bell et al. [16] who found that the risk of major congenital anomaly increase among offspring of women with pre-existing diabetes, overall one in 13 singleton deliveries (7.7%) was affected. Also Wu et al. [17] found that pregestational diabetes and, to a lesser extent, GDM were associated with several subtypes of congenital anomalies of the newborn. These findings suggest potential benefits of preconception counseling in women with pre-existing diabetes or at risk for gestational diabetes for the prevention of congenital anomalies.

As regard to hypertension during pregnancy, the current study found that hypertensive is statically insignificant with non-cardiac fetal malformations. This finding is in contrast with the study by Bellizzi et al. [18] who studied 1152 women with chronic hypertension, 6163 women with preeclampsia, 765 women with eclampsia and 294 with preeclampsia superimposed on chronic hypertension & found that newborns of women with chronic maternal hypertension are at higher risk of fetal malformations The multivariable analysis strengthened the association between the chronic hypertension with superimposed preeclampsia and fetal malformations.

In our study, the major non-cardiac congenital anomalies observed were CNS (24%) followed by skeletal anomalies, abdominal and genitourinary (16%), facial deformity (12%), thorax malformation, and hydrops fetalis (8%). These findings are consistent with those of Yu et al. [8] who found that major malformations were CNS (24.14%)followed by facial anomalies (19%), genitourinary (16%), skeletal deformity (11%) and digestive system (6%) and Sadek et al. [11] who found that major anomalies are CNS followed by skeletal, abdominal, fascial and hydrops fetalis.

The current study revealed that 2D US made definite diagnoses of about 50% of genitourinary, abdominal, and thorax malformations, while 4D US made definite diagnoses of most facial and CNS anomalies.

Many previous studies discussed congenital anomalies in 2D-US with only suspected cases examined by 4D-US [8, 9, 11]; in contrast, in our study, we did both 2D-US and 4D-US for all cases. Also, previous studies had done the examination as part of a screening program [9], but in our study, we selected only high-risk pregnant females according to their clinical history. Lastly, most previous studies discussed isolated fetal system anomalies [19,20,21], but in our study, we collected many systems.

This study still has several limitations, though. Initially, we only looked at pregnant women (between 24 and 34 weeks), which failed to differentiate between the diagnostic value of 2D and 4D ultrasound screening in the first and late third trimesters. Other risk factors, such as smoking, radiation and hereditary diseases were not taken into account. After 32 weeks, a 3D or 4D scan can be more difficult because the bay is beginning to drop into the pelvis and is taking up more space, and the amniotic fluid levels begin to reduce. In cases with oligohydramnios and renal anomalies, a 3D/4D scan can be more difficult because the amniotic fluid decreases around the baby. The diagnostic value of 2D-US and 4D-US in the screening of non-cardiac fetal congenital abnormalities should thus be the subject of further study.

Conclusions

The diagnosis rate of fetal abnormalities can be significantly increased by combining two-dimensional ultrasound with four-dimensional ultrasound. Avoiding risk factors that raise the likelihood of fetal abnormalities should take priority for pregnant women with high risk factors. To lower the incidence of fetal abnormalities, prenatal screening and diagnosis should be standardized.