ANTENATAL ULTRASOUND SCREENING FOR ANOMALIES AMONG SINGLETONS – RESULTS OF A PROSPECTIVE STUDY  

Balakumar.K
Balku's Scan

Address for Correspondence
Dr.Balakumar.K
Balku's Scan
PVS Hospital, Calicut, Kerala 673 002.
E mail : balkumardr@sify.com

ABSTRACT

A prospective study of 15 years and 7 months duration was carried out to define the incidence and systemic distribution of fetal anomalies in Kerala (a southwestern coastal state of India). Among the live 30, 030 singleton pregnancies of 9 to 41weeks’ gestation subjected to ultrasound scanning, the incidence of major fetal anomalies was found to be 2.59% (p < 0.05). The central nervous system was the commonest involved (39.21%), followed by the genitourinary tract (18.09%) and the skeletal system (11.79%) anomalies. The incidence of neural tube defects was 17.27%. A significant number of fetuses showed acrania (0.82%) and jugular lymphatic obstruction sequence (2.57%). The sensitivity and the specificity values of the screening results were 72.2% and 98.6% respectively. The single author has carried out the observation and analysis.

KEY WORDS: Fetal anomalies, prenatal diagnosis, ultrasonography, ultrasound scan, antenatal screening.

AIM

                        The study was aimed at defining the incidence of major fetal anomalies in northern Kerala that could be detected by routine ultrasound scanning. The quantification of the true incidence and the definition of the systemic preponderance help in stratification of the affected fetuses for the sake of prognostication and tailoring of management policies.

MATERIALS AND METHODS

                        Those pregnancies referred for routine as well as targeted imaging contributed the population for this study. Only live singleton pregnancies of 9 to 41 weeks' gestation were analysed. Plural pregnancies were excluded because of statistically lower number. The amniotic fluid volume was assessed subjectively. Those with vesicular mole and intrauterine demise were excluded. Metabolic diseases and other abnormalities without evident structural variations were also excluded. Minor anomalies of minimal surgical or cosmetic significance were not included. The fetuses were selected at random. Those with major anomalies were serially assessed and followed up for confirmation of the diagnosis. Suspicious findings were verified from peroperative findings, autopsy or follow up records.

                        The machines used were Philips SDR 1550 and Philips P 600 (transabdominal linear convex probes of 3 - 3.5 and transvaginal probe of 5.5 - 6.5 MHz along with color Doppler facilities). The total population studied was 34, 240 fetuses of which 33, 030 were singletons and 1, 210 were plural pregnancies. The single author has conducted this prospective study from January1985 through August 2000 (15 years and 7 months).

OBSERVATIONS

                        The majority of the cases referred for scanning were for confirmation of the gestational age and for exclusion of associated pathologies and anomalies. A more specific indication was the disproportionate uterine size compared to the period of amenorrhoea. The other common indications were vaginal bleeding and discrepancies of growth. Those mothers with history of previous anomalous fetuses, perinatal infections or exposure to teratogens formed only a small group.

                        Polyhydramnios of moderate to severe degree was noted in 450 pregnancies of the total sample studied. The central nervous system and gastrointestinal system were commonly involved in these cases. No ultrasonographically detectable cause could be defined in few. Significant degree of oligohydramnios was seen in 85 pregnancies. Genitourinary tract anomalies were found as the major contributor for this. Pregnancies with severe degree oligohydramnios often ended up with early intrauterine demise, so that the cause was unidentifiable by echoes in many instances.

                        There were 857 anomalous fetuses in the population studied. The system wise distribution is represented in the Chart No.1. The smaller entities were grouped as “others”,

including lymphatic and respiratory system anomalies. The details are shown in the Table No. 1.

Chart No.1 showing the systemic distribution

Systems involved	No. of fetuses affected	Percentage
CNS	336	39.21
GUT	155	18.09
SKELETAL SYSTEM	101	11.79
GIT	091	10.62
CVS	045	05.25
OTHERS	129	15.05
TOTAL	857	02.59 % (overall)

        Table No.1. Details of systemic involvement among 33,030 live singletons.

                        The commonest system involved was the central nervous system (CNS) in 336 fetuses. The neural tube defects (NTD) were diagnosed in 148 and among them anencephaly was seen in 108 fetuses. There were 14 fetuses with cephaloceles, 11 with meningomyeloceles and 6 with spina bifida. Acrania (exencephaly) was diagnosed in 7 fetuses of first trimester. Hydrocephalus was evident in 104 fetuses. Twenty-five fetuses showed microcephaly and an equal number had holoprosencephaly. The CNS anomalies are detailed in the following table No.2.

CNS anomalies	No. of fetuses affected	Percentage
Anencephaly	108	12.60
Cephalocele	14	1.63
Meningo\ myelocele	11	1.28
Spina bifida	06	0.70
Iniencephaly	02	0.23
Acrania	07	0.82
Hydrocephalus	104	12.14
Dandy Walker Malformation	07	0.82
Arnold Chiari malformation	04	0.47
Corpus callosal agenesis	02	0.23
Microcephaly	25	2.92
Holoprosencephaly	25	2.92
Porencephaly	05	0.74
Hydranencephaly	03	0.35
Schizencephaly	03	0.35
Kyphosis	03	0.35
Teratoma	03	0.35
Arachnoid cyst	03	0.35
Choroid plexus cyst (bilateral)	03	0.35
Total	336	39.20 %

Table No. 2. The distribution of the CNS anomalies                  

                        The genitourinary tract (GUT) anomalies were diagnosed in 154 fetuses (Table No.3). Among them, hydronephrosis was seen in 81 fetuses. Fetuses with dilated renal pelves of less than 8 mm before 32 weeks and less than 10 mm after 32 weeks were excluded from this study. The cystic renal diseases were documented in 25 fetuses. The commonest presentation was the presence of multiple cysts of varying size. The diagnosis of infantile polycystic kidney disease (IPKD) could be specifically made on typical sonographic features. Bladder outlet obstruction was detected in 22 fetuses. There were 14 fetuses having renal agenesis in association with severe degree oligohydramnios. Five fetuses showed megacystis leading to massive distension of the abdomen. Ureterocele was diagnosed in a fetus of 36 weeks gestation causing unilateral hydronephrosis. Only one fetus showed ectopia vesica.

GUT anomalies	No. of fetuses affected	Percentage
Hydronephrosis	81	9.45
Cystic kidneys	25	2.92
Bladder outlet obstruction	22	2.57
Renal agenesis	14	1.63
Megacystis	05	0.58
Echogenic kidneys	06	0.70
Extrophy	01	0.12
Ureterocele	01	0.12
TOTAL	155	18.08 %

Table No. 3. Distribution of GUT anomalies

                        Skeletal system was involved in 101 fetuses (Table No.4). The commonest presentation was as limb reduction abnormalities in 56. There were 16 cases of achondroplasia, 8 cases of achondrogenesis, 4 cases of osteogenesis imperfecta and 3 cases of thanatophoric dysplasia. Thoracic dysplasia was the main presentation in 13 fetuses. Only one fetus showed the classical predictors of hypophosphatasia. A more precise typing of the fetuses with limb shortening was difficult antenatally.

SKELETAL anomalies	No. of fetuses affected	Percentage
Limb bone shortening	56	6.53
Achondroplasia	16	1.87
Achondrogenesis	08	0.93
Osteogenesis imperfecta	04	0.47
Thanatophoric dysplasia	03	0.35
Thoracic dysplasia	13	1.52
Hypophosphatasia	01	0.12
TOTAL	101	11.78 %

Table No. 4. The distribution of skeletal system anomalies

                        The gastrointestinal tract (GIT) anomalies in 91 fetuses (Table No. 5) showed a preponderance of esophageal  (26 fetuses) and intestinal atresias (25 fetuses). Diaphragmatic hernia was diagnosed in 25 fetuses. All of then presented with considerable degree of polyhydramnios. There were 8 fetuses with omphalocele, 4 fetuses with gastrochisis and 3 fetuses showing features of meconium peritonitis.

GIT anomalies	No. of fetuses affected	Percentage
Esophageal atresia	26	3.73
Duodenal atresia	13	1.52
Intestinal atresia	12	1.40
Diaphragmatic hernia	25	2.92
Omphalocele	08	0.93
Gastrochisis	05	0.47
Meconium peritonitis	03	0.35
TOTAL	91	10.62 %

Table No. 5. The distribution of GIT anomalies

                        The cardiovascular system (CVS) was affected in 45fetuses (Table No. 6) in the form of major structural abnormalities and arrhythmias. Cardiomegaly was seen in 8, dextrocardia in 4, septal defects (atrial as well as ventricular) in 8, right atrial dilation in 8 (of which 3 were showing features of Ebstein’s anomaly), hypoplastic left ventricle in 3 and echogenic mitral valves in 2 fetuses. Ectopia cordis was diagnosed in 3 fetuses. Tetralogy of Fallot was diagnosed in two fetuses of 34- 38 weeks. Seven fetuses showed arrhythmias.

                         The miscellaneous group included 129 anomalous fetuses (Table No.7). Among them, 34 fetuses had classical features of hydrops (non-immune). Jugular lymphatic obstruction sequence was diagnosed in 22 fetuses. Amniotic band disruption and limb body wall complexes were diagnosed in 10 fetuses. Four female fetuses were having intrapelvic cystic masses. Multiple systems were involved in 37 fetuses making it difficult to classify the anomalies. One fetus showed the presence of an adrenal mass which was characteristic of a hemorrhage on serial postnatal scanning. There were three fetuses with features of cystic adenomatoid malformation of the lung. Isolated plural or pericardial effusion was observed in 11 fetuses. Macrosomia was detected in 7 fetuses.

CVS anomalies	No. of fetuses involved	Percentage
Cardiomegaly	08	.93
Dextrocardia	04	0.47
Ectopia cordis	03	0.35
Atrial septal defect	05	0.58
Ventricular septal defect	03	0.35
Fallot’s tetralogy	02	0.23
Hypoplastic left ventricle	03	0.35
Right atrial dilation	08	0.93
Echogenic mitral valve	02	0.23
Arrhythmias	07	0.82
TOTAL	38	5.25 %

Table No. 6. The distribution of CVS anomalies

OTHER anomalies	No. of fetuses affected	Percentage
Hydrops	34	3.97
JLOS	22	2.57
Multisystemic	37	4.32
Amniotic band disruption	07	0.82
Limb body wall complex	03	0.35
Macrosomia	07	0.82
Ovarian cyst	04	0.47
CAM lung	03	0.35
Adrenal hemorrhage	01	0.12
Pleural effusion	07	0.82
Pericardial effusion	04	0.47
TOTAL	129	15.05 %

Table No. 7. Distribution of “other” anomalies

                        The postnatal follow up revealed that 9 cases of major anomalies were missed on routine screening. These were two cases of spina bifida, two cases of esophageal atresia, a case of bladder extrophy, one case of arthrogryposis multiplex congenita, a case of atrial septal defect, two cases of small ventricular septal defects and a case of unilateral facial hypoplasia.

DISCUSSION

                        Many reports have highlighted the advantage of routine fetal surveillance by antenatal ultrasonography for various indications (Saari-Kemppainen et al, 1990; 1995; Constantine & McCormack 1991; Luck 1992; Stoll et al 1995, Behrens et al 1999). Some studies have argued against the usefulness of the same (Ewigman et al 1990, Bucher & Schmidt 1993, Ewigman et al 1993). The interpretation and comparison of the results of these studies are difficult because of varying criteria. The present study was limited to determining the incidence and systemic distribution of major anomalies in the specified population. The advantages or disadvantages regarding routine antenatal screening is not analysed here. This question remains unsolved till this date (Carolyn DiGuiseppi 2000). The incidence of polyhydramnios among the singleton pregnancies analysed was 1.36 %. This is slightly higher than the incidence of 0.93% published after an objective assessment of 9000 subjects (Hill et al 1987). As the present analysis was based on the subjective impression of the author, a true comparison is difficult. However, for practical purposes the author has found the subjective assessment of the liquor volume to be equally informative if the observer is well-experienced (Larmon & Rosa 1998).

                        The overall incidence of the major fetal anomalies in this study was 2.59% which falls with in the range reported in the literature (Reyneir et al 1994; Whiteman & Reece 1994; Anderson et al 1995). Different authors have reported an incidence ranging from 1.27 to 3% in larger series. The true incidence should have been more if the intrauterine demises, molar pregnancies and multiple gestations were included. These were excluded from this study in order to avoid uncertainties and to evolve statistically significant values. This study is unique because of the fact that the author alone has screened and followed up the population selected at random for a longer period of duration. On the other hand, the published series in the literature usually depended on collective data contributed by various observers of different institutions. In a multicentric randomised study of 15,151 fetuses, it was found that only 35% of anomalous fetuses could be detected before birth (Frigoletto et al 1993).

                        The central nervous system was the commonest involved in this study (39.20 %) as reported by all major series (Weston et al 1993). Among them, the NTD showed predominance. Out of the sonographically identifiable neural tube defects such as anencephaly, cephalocele, meningocele, spina bifida, iniencephaly and acrania, the former is typical by its increased frequency of incidence (32.14 %) and higher sensitivity and specificity of early diagnosis. The incidence of spina bifida in its severity as aperta in the form of meningo or meningomyelocele was 3.27 % and in its milder form as occulta was 1.79 %. If the overall incidence of spina bifida is considered, it contributed for 1.98% of the major anomalies among singletons. This is almost equal to that was reported from United States (Stein et al 1982; Lorber & Ward 1985). The incidence among the newborns is decreasing with the widespread use of antenatal ultrasound scanning in the past three decades. A noticeable number of fetuses (7 in number) were diagnosed to have acrania, which is an invariably lethal anomaly that could be diagnosed by early first trimester (Balakumar 1992). This anomaly could be easily mistaken for anencephaly in the late first trimester (Harris et al 1993). Hydrocephalus was the second commonest (30.95 %) anomaly among CNS after anencephaly. This usually manifests in second trimester and needs serial assessments for diagnosis and prognostication. The overall incidence 0.31 is agreeing with another report of 0.3 to 0.8 per 1000 births (Terrone & Perry 1998). Corpus callosal agenesis and Dandy Walker malformations were lesser in this population, though the former shows an incidence of 1-5% of all pregnancies and the latter has an incidence of 1 in 30,00 births (Terrone & Perry 1998; Bertino 1988). The commonest subtype of holoprosencephaly noted in 25 fetuses was the alobar variety. A study published earlier showed the incidence of holoprosencephaly as 1 in 250 concepti (Matsunga & Shieota 1977), an alarmingly high rate compared to this analysis. This rate decreases by the time of birth because of early spontaneous abortion (Terrone & Perry 1998). Isolated bilateral choroid plexus cysts were seen in only two fetuses (0.23%), contrary to the reported incidence of 3- 4% in second trimester pregnancies and 1- 2% in general population (Porto et al 1993; Sharony 1997). Microcephaly contributed for a significant share (7.44 %). The diagnosis of microcephaly was considered if the head circumference was more than 3 standard deviations below the mean, on serial evaluation. A normal cephalometry in early trimesters doesn’t exclude the possibility of microcephaly (Bromley & Benaceraff 1995).

                        The genitourinary tract was seen commonly involved (18.08 %) after the CNS. The commonest presentation was as unilateral (pelviureteric junction obstruction) or bilateral hydronephrosis (bladder outlet obstruction) in 52.25%. This is consistent with the report that the commonest GUT anomaly is hydronephrosis (Hanna & Jeffs 1975; Scott & Renwick 1993). A certain degree of minimal prominence of the collecting system (less than 8mm before 32 weeks and less than 10 mm after wards) was considered insignificant. This is supported by the observation that 43.1% of pelvicalyceal dilation is likely to regress postnatally (Harding et al 1999). Cystic renal diseases diagnosed among 25 % of fetuses showed overlapping features except in cases of IPKD (Balakumar 1992). Bladder outlet obstruction was detected by early second trimester (Balakumar 1990). Severe degree oligohydramnios in the absence of urinary bladder shadow on repeated attempts was associated with bilateral renal agenesis. The incidence of this anomaly was 1.63 % in this study compared to an incidence of 0.1 to 0.3 per 1000 live births in another report (Carter & Evans 1981; Wilson & Baird 1985).

                        The skeletal system anomalies were the third commonest contributor for 11.78 % of the anomalous fetuses. The overall incidence of skeletal anomalies is reported to be 2.4 per 10,000 births (Rust et al 1998) in the literature. Most of them manifested by shortening of the long bones. Few cases of achondroplasia and lethal achondrogenesis could be diagnosed with 100% specificity (Balakumar 1990). Thoracic dysplasias were of significantly noticeable incidence (1.52 %). However, the correct antenatal classification of the skeletal dysplasias was often difficult (Bulas & Fonda 1997).

                        The gastrointestinal tract anomalies (10.62 %) were mainly in the form of atresias associated with considerable degree of polyhydramnios (Balakumar 1989, 1992). The reported incidence of GIT involvement is 5- 7% among all anomalies (Skupski 1998). Few fetuses with esophageal atresias showed a small stomach shadow because of tracheo-esophageal fistula. Diagnosis of diaphragmatic hernia was more specific on serial scanning (Balakumar 1992). A recent study has estimated the overall incidence of this anomaly as 1 in 2,200 births (Cannon et al 1996). The prenatal detection rate is reported to be 15.2 –78.9% in a metaanalysis (Skari, et al 2000). The incidence of abdominal wall defects is also low here (1.4 %) as reported by a European study (Calzolari et al 1995).

                        The incidence of cardiovascular system anomalies were low (5.25 %) in the analysed group. This was due to the fact that the population surveyed included random sample and not high-risk group alone. It has been established that only significant structural anomalies could be diagnosed antenatally and that also in the later period of gestation (Balakumar 1991, 1994). Since the early part of this study was done with a black and white scanner, it is possible that a few lesions would have been missed. The postnatal follow up of cardiac anomalies was also inadequate. In a recent study involving 22, 050 fetuses followed up by clinical and autopsy findings the incidence of cardiac anomalies was 7.6 cases per 1000 live births (Yagel et al 1997). It has to be stressed that the four-chamber view and the outflow tracts and aortic arch details supplemented by color Doppler-mapping increase the diagnostic sensitivity of cardiac anomalies. Early trimester transvaginal scanning also enhances the detection rate (Bronshtein et al 1993).

                        Among the miscellaneous group (15.05 %) the majority was diagnosed as immune hydrops (3.98 %). There were no cases of immune hydrops in the sample analysed. This was followed by 2.57 % of fetuses with classical features of jugular lymphatic obstruction sequence. The diagnosis of this entity could be made out in late first trimester. One case was diagnosed at 13 weeks (Balakumar 1993). The usual period of diagnosis was 16 to 20 weeks’ gestation in a recent report (Suzuki et al 1998). It may be noted that the incidence of JLOS in this population is significant (Balakumar 1993). Because of the fact that these fetuses have an increased chromosomal abnormality and usually undergo spontaneous abortion in early pregnancy, the number of affected fetuses after birth is much less. All the fetuses with intrapelvic cystic masses were females. In one fetus, the cyst was occupying the sub hepatic region. Postnatal surgery revealed the cysts as simple serous cysts in two and dermoid in one fetus. Multisystemic anomalies in 37 fetuses hinted at the possibility of chromosomal abnormalities among some fetuses. The figures in this category couldn’t be derived since the chromosomal analysis was incomplete. Unilateral cystic adenomatoid malformation of the lung (Type 1) was diagnosed in three fetuses. This anomaly accounts for 25% of congenital lung lesions in the literature (Stocker et al 1977, Wolf et al 1980). Macrosomia was significantly lesser (0.82 %) when compared to that of 1-2% incidence in developed countries.

                  The Medline search didn’t yield a similar study of longer duration conducted by a single author in the literature. The results were compared with the other published reports using the test for proportion. It was found that the overall incidence of major anomalies in the group studied showed a highly significant value (p < 0.05). This can be explained on the basis of the population characteristics and sample features. When compared to an earlier analysis published in 1999, there is a slight increase in the incidence (Balakumar 1999). This could be due to the increased awareness among the doctors and the availability of better machines as the technology advances. The variation of the incidence rates of systemic involvement in different ethnic groups demands further prospective trials. The sensitivity is considerably affected by the skill of the person involved, the demonstrability of the anomalies, the population characteristics and the method of calculation adopted (Dooley 1999).

CONCLUSIONS

(1). The overall incidence of major anomalies among singleton pregnancies of 9 - 41 weeks’ gestation was 2.59 % in this region of Northern Kerala (p < 0.05).
(2). The commonest system affected was the CNS, followed by the genitourinary tract and skeletal system anomalies. Spina bifida shows a relatively lower incidence here.
(3). The CVS showed a lower incidence because of low sensitivity of detection and inadequate follow up.
(4). An increased incidence of acrania and jugular lymphatic obstruction sequence was noted. Both these conditions being invariably lethal, the awareness may contribute for earlier detection and intervention.
(5). This study recommends the use of a minimum of one antenatal ultrasound screening preferably in the late first trimester to avoid the antenatal complications or the birth of an abnormal baby.

This study is unique due to the fact that it comprises a statistically significant population observed and analysed by a single author for a period of 15 years and 7 months.

REFERENCES

1.Anderson N, Boswell O, Duff G. Prenatal sonography for the detection of fetal anomalies: Results of a prospective study and comparison with prior series. AJR 1995; 165 (4): 943-50.

2.Balakumar K. Antenatal diagnosis of acrania. Ind Pediatr 1992; 23: 493-6.

3.Balakumar K. Antenatal diagnosis of atrial septal defect. Ind J Radiol Imaging 1994; 4 (10): 52-3. 

4.Balakumar K. Antenatal diagnosis of bowel atresia. Ind Pediatr 1992; 29: 1579-82.

5.Balakumar K. Antenatal diagnosis of Ebstein’s anomaly. Ind Pediatr 1991; 28: 1055-8.

6.Balakumar K. Antenatal diagnosis of Parenti-Fraccaro type of achondrogenesis. Ind Pediatr 1990; 27: 496-99.

7.Balakumar K. Jugular lymphatic obstruction: Antenatal diagnosis and its incidence in Kerala. Ind J Radiol Imaging 1993; 3 (2), 89-93.

8.Balakumar K. Major fetal anomalies among singleton pregnancies of Kerala. Ultrasound International 1999; 5 (4): 198-207.

9.Balakumar K. Posterior urethral valves- comparison of two cases in early intrauterine period. Ind J Obstet Gynecol 1990; 40 (3): 319-21.

10.Balakumar K. Prenatal diagnosis of Bochdalek’s type of diaphragmatic hernia. Ind Pediatr 1992; 29: 1143-5.

11.Balakumar K. Prenatal diagnosis of duodenal atresia. Ind Pediatr 1989; 26 (9): 950-2.

12.Balakumar K. Prenatal diagnosis of jugular lymphatic obstruction sequence at 13 weeks’ gestation. Indian Pediatr 1991; 28: 1065-8.

13.Balakumar K. Prenatal diagnosis of Meckel’s syndrome. Ind Pediatr 1992; 29: 487-91.

14.Behrens O, Steiner C, Bohmer S, Muhlhaus K. Efficacy of ultrasound screening in pregnancy. Zentralbl Gynnakol 1999; 121 (5): 228-32.

15.Bertino RE, Nyberg DA, Cyr DR, et al. Prenatal diagnosis of agenesis of the corpus callosum. J Ultrasound Med 1988; 7 (5): 251-60.

16.Bromley B, Benaceraff BR. Difficulties in the prenatal diagnosis of microcephaly. J Ultrasound Med 1995; 14 (4): 303-6.

17.Bronshtein M, Zimmer EZ, Gerlis LM, Lorber A, Drugan A. Early ultrasound diagnosis of fetal congenital heart defects in high-risk and low risk pregnancies. Obstet Gynecol 1993; 82 (2): 225-9.

18.Bucher H, Schmidt JG. Does routine ultrasound scanning improve outcome in pregnancy? Meta-analysis of various outcome measures. BMJ 1993; 307: 13-7.

19.Bulas DI, Fonda JS. Prenatal evaluation of fetal anomalies. Pediatr Clin North Am 1997; 44: 537-54.

20.Calzolari E, Bianchi F, Dolk H, et al. Omphalocele and gastrochisis in Europe: A survey of 3 million births, 1980-90. Am J Med Genet 1995; 58: 187.

21.Cannon C, Dildy GA, Ward R, et al. A population based study of congenital diaphragmatic hernia in Utah: 1988-94. Obstet Gynecol 1996; 87: 959.

22.Carolyn DiGuiseppi. [Clinical Preventive Services] Screening Ultrasonography in Pregnancy. http://cpmcnet.columbia.edu/texts/gcps/gcps0046.html

23.Carter CO, Evans K. Birth frequency of bilateral renal agenesis. [letter] J Med Genet 1981; 18 (2): 158.

24.Constantine G, McCormack J. Comparative audit of booking and mid-trimester ultrasound scans in the prenatal diagnosis of congenital anomalies. Perinatal Diagnosis 1991; 11: 905-14.

25.Dooley SL. Routine ultrasound in pregnancy. Clin Obstet Gynecol 1999; 42 (4) 737-48.

26.Ewigman B, LeFerve, Hesser J. A randomised trial of routine prenatal ultrasound. Obstet Gynecol 1990; 76: 189-94.

27.Ewigman BG, Crane JP, Frigoletto FD, LeFevre LM, Bain RP, McNellis D. The RADIUS Study Group. Effect of prenatal ultrasound screening on perinatal outcome. New Eng J Med 1993; 329: 821-827.

28.Frigoletto FD, et al. Effect of prenatal ultrasound screening on perinatal outcome. N Engl J Med 1993; 329: 821.

29.Hanna MK, Jeffs RD. Primary obstructive megaureter in children. Urology 1975; 6: 419.

30.Harding LJ, Malone PS, Wellesley DG. Antenatal minimal hydronephrosis: is its follow-up an unnecessary cause of concern? Prenat Diagn 1999; 19(8): 701-5.

31.Harris CP, Townsend JJ, Carey JC. Acalvaria: a unique congenital anomaly. Am J Med Genet 1993; 46 (60; 649-9.

32.Hill LM, Breckle R, Thomas ML, et al. Polyhydramnios: Ultrasonographically detected prevalence and neonatal outcome. Obstet Gynecol 1987; 69: 21-5.

33.Larmon JE, Rosa BS. Clinical utility of amniotic fluid assessment. Obstet Gynecol Clinics of North Am 1998; 25 (3): 639-66.

34.Lorber J, Ward AM. Spina bifida: a vanishing nightmare? Arch Dis Child 1985; 60 (11): 1086-91.

35.Luck CA. Value of routine ultrasound scanning at 19 weeks: a four-year study of 88-49 deliveries. BMJ 1992; 304: 1474-78.

36.Matsunaga E, Shieota K. Holoprosencephaly in human embryos: Epidemiologic studies of 150 cases. Teratology 1977; 16: 261.

37.Porto M, Murata Y, Warneke LA, et al. Fetal choroid plexus cysts: An independent risk factor for chromosomal anomalies. J Ultrasound 1993; 21: 103.

38.Reyneir JC, Philip N, Scheiner A, Aurran Y, Chabal F, Maron A, Gombert A, Ayme S. Impact of prenatal diagnosis by ultrasound on the prevalence of congenital anomalies at birth in southern France. J Epidemiol Community Health 1994; 48(3): 290-6.

39.Rust OA, Perry Jr. KG, Roberts WE. Tips in diagnosing fetal skeletal anomalies. Obstet Gynecol Clin of North Am 1998; 25 (3): 553-71.

40.Saari-Kemppainen A, Karjalainen O, Ylostalo P, Heinonen OP. Ultrasound screening and perinatal mortality: controlled trial of systemic one stage screening in pregnancy. The Helsinky Ultrasound Trial. Lancet 1990, 336: 387-391.

41.Saari-Kemppainen A. Use of antenatal care services in a controlled ultrasound screening trial. Acta Obstet Gynecol Scand. 1995; 74: 12-14.

42.Scott JE, Renwick M. Urological anomalies in the Northern Region Fetal Abnormality Survey. Arc Dis Child 1993; 68 (1 Spec No): 22-6.

43.Sharony R. Fetal choroid plexus cysts. Is a genetic evaluation indicated? Prenatal Diagnosis 1997; 17: 519-24.

44.Skupski DM. Prenatal diagnosis of gastrointestinal anomalies with ultrasound. What have we learned? Ann N Y Acad Sci 1998; 18: 847: 53-8.

45.Stein SC, Feldman JG, Friedlander M, Klein RJ. Is myelomeningocele a disappearing disease? Pediatrics 1982; 69: 511.

46.Stocker JT, Madewell JE, Drake RM. Congenital cystic adenomatous malformation of the lung. Human Pathol 1977; 8 (2): 155-71.

47.Stoll C, Dott B, Alembik Y, Roth MP. Evaluation of routine prenatal diagnosis by a registry of congenital anomalies. Prenatal Diagnosis 1995; 15: 791-800.

48.Suzuki N, Tsuchida Y, Takahashi A, Kuroiwa M, Ilkeda H, Mohara J, Hatakeyama S and Koizumi T. Prenatally diagnosed cystic lymphangioma in infants. J Pediatr Surg 1998; 33 (110); 1599-1604.

49.Terrone AD, Perry KG. Ultrasound evaluation of the fetal central nervous system. Obstet Gynecol Clin of North Am 1998; 25 (30: 479-97.

50.Weston MJ, Porter HJ, Andrews WS, Berry PJ. Correlation of antenatal ultrasonography and pathological examination in 153 malformed fetuses. J Clin Ultrasound 1993; 21 (6): 387-92.

51.Whiteman VE, Reece EA. Prenatal diagnosis of major congenital malformations. Curr Opin Obstet Gynecol 1994; 6 (5): 459-67.

52.Wilson RD, Baird PA. Renal agenesis in British Columbia. Am J Med Genet 1985; 21 (1): 153-69.

53.Wolf SA, Hertzler JH, Philippart AI. Cystic adenomatous dysplasia of the lung. J Pediatr Surg 1980; 15 (6): 925-30.          

54.Yagel S, Weissman A, Robstin Z, et al. Congenital heart defects- natural course in –utero development. Circulation 1997; 96: 550.

55.Skari H, Bjornland K, Haugen G, Egeland T, Emblem R. Congenital diaphragmatic hernia: A meta-analysis of mortality factors. J Pediatr Surg 200; 35 (8): 1187-1197.