Birth defects are relatively common, affecting 3% to 5% of live-births in the United States 1 and 2.1% in Europe 2. For more than two decades, birth defects have been the leading cause of infant mortality in the US 3. Birth defects are also the leading cause of infant mortality in the Region of Lombardy, northern Italy. In 1998, 2800 infants in the Region of Lombardy died in the first year of life; of these 852 had birth defects (16/10,000) 4. The morbidity and disability experienced by surviving children also has a major public health impact.

Around 40% to 60% of birth defects are of unknown origin; 20% are attributed to a combination of heredity and other factors; 7.5% to single gene mutations; 6% to chromosome abnormalities; and 5% to maternal illnesses, such as diabetes or infection, or use of anticonvulsant or other drugs 567.

The prevalence rate of birth defects is increasingly used as an indicator of exposure to teratogens of various kinds, particularly pesticides but also pharmaceuticals 8.

Registries and surveillance systems are the only way to obtain population-based data on birth defects, since birth certificates have been shown to be inadequate 9. We set up a registry in 1999, covering part of the Region of Lombardy, to monitor the annual prevalence rates of birth defects. The aims of the present study are (a) to briefly describe the structure of the system used to gather case information and generate birth defect data emphasizing features that ensure data quality, (b) to present a preliminary analysis of prevalence rates for selected birth defects in children born in 1999 in the Provinces of Mantova, Sondrio and Varese (Region of Lombardy); and (c) to assess the quality of data produced by performing a completeness evaluation using birth certificates for comparison, and comparing rates with those published by long established birth defect registries.

A birth defect is defined by the registry as a structural or chromosomal anomaly present at birth and recognized during the first year of life. The registry records all birth defects in live births. However, the present analysis concerns selected defects: those considered major by Rasmussen et al 10 and the International Clearinghouse for Birth Defects 11, except that limb deficiencies are not considered, due to problems with diagnosis and coding in our dataset.

Use of birth certificates to check completeness added two new cases to the Lombardy birth defects registry. The quality and the completeness of birth certificates is known to vary considerably 24. We found a large number of false positives and also massive under-reporting, which shows that birth certificates are not a reliable single source for ascertaining congenital malformations 24. However their availability allowed us to perform a natural experiment to assess our registration system and identify weaknesses in data collection 25.

We discuss our birth defects prevalence findings in relation to those from three other birth defect registries: Georgia USA 23, Hawaii 23 and Finland 11. There are several reasons for this. All three are large (national or state) long-established population-based national registries, with a history of quality scientific publications. They also use differing data collection methods and cover geographically disparate areas.

The overall prevalence at birth of the 40 selected congenital defects in our study area in 1999 was 204.9/10,000. This compares with 223.9/10,000 for the birth defects registry of Georgia USA in 1995–1999 23, 233.6/10,000 for the registry of Hawaii 23 from 1995 to 1999, and 103.5/10 000 for birth defects recorded in Finland in 1998 11.

Cardiovascular system defects were by far the most common birth defects in our population. Prevalence rates for these defects were grossly similar to rates published previously 23, except for ventricular septal defects (VSD), for which we found particularly high overall rates (58.3/10,000). The latter are nonetheless fairly comparable with those reported by Florida (41.6/10,000), Georgia (35.6/10,000) and Hawaii (43.4/10,000) 23. The elevated prevalence of VSD in our study areas is probably due to over-diagnosis: routine use of echocardiography on virtually all newborn infants has resulted in the identification of large numbers of small and clinically unimportant VSDs. Subsequent echocardiography results in the inclusion of clinically unimportant defects (that close spontaneously). Progress in clinical management and more frequent prenatal diagnosis have reduced neonatal mortality, increasing the prevalence at birth of these defects, while generally only severe congenital heart defects diagnosed in utero are aborted 26. These findings indicate a strong need to standardize both diagnostic and registration criteria for congenital heart malformations, as also suggested by Hofmann 27.

We found rates of 6.7/10,000, 3.3/10,000 and 7.5/10,000 for transposition of great arteries, endocardial cushion defects, and coarctation of aorta, respectively. These figures compare with lower birth prevalences for transposition of great arteries in Finland (4.0/10,000; endocardial cushion defects not reported), and a higher rate for endocardial cushion defect (5.5/10,000) but lower rates for transposition of great arteries (5.4/10,000) and coarctaction of aorta (5.6/10,000) in Georgia. In cases of complete transposition, the aorta arises from the right ventricle and the pulmonary artery arises from the left ventricle, and there is an associated ventricular septal defect, which in all eight of our registered cases was large. Botto et al. 28 observed an increase birth prevalence of atrial and ventricular defects from 1968 to 1995 in the population of Atlanta but no change in the rate of grand artery transpositions.

We found low birth prevalence rates for tetralogy of Fallot (2.5/10,000) and hypoplastic left heart syndrome (0.8/10,000) compared with the corresponding figures of 3.3/10,000 and 4.7/10,000 in Finland, 4.5/10,000 and 3.2/10,000 in Georgia, and 3.1/10,000 and 1.5/10,000 in Hawaii. Our rate of 2.5/10,000 is comparable with other European prevalence rates of 2.56/10,000 and 2.45/10,000 for Central-Eastern France and Sweden respectively 29. The study by Hoffman 27 reviewed 41 studies on cardiac malformation and found prevalence rates for tetralogy of Fallot ranging from 2.91/10,000 to 5.77/10,000, with a mean of 4.21/10,000.

The birth prevalence of hypospadias varies widely (2.0–39.7/10,000) 30. We found very high rates of hypospadias in accord with data from Georgia (35.1/10,000) 23 but in stark contrast to the low figure of 2.6/10,000 from Finland 11.

The study by Pierik et al. 31 addressed the highly variable hypospadias rates in Holland, studying a cohort of all newborn in Rotterdam over a two year period. They found a high rate (38/10,000) which is comparable to ours. They concluded that the variation in hypospadias birth prevalence in Holland is due both to differences in case ascertainment and real geographic variation.

The comparability of reported rates for hypospadias is poor, however there may be an important underlying geographic variation which cannot be properly addressed until ascertainment and diagnostic criteria (inclusion or exclusion of minor cases) are standardized 30. Hypospadias could be related to exposure to antiandrogenic factors that interfere with androgen activity 32. There is also evidence that increases in these birth defects are linked to increased risk of testicular cancer, both of which may be related to exposure to environmental substances having estrogen-like effects 33. Genetic factors may also predispose to the development of hypospadias 34.

Our overall figure for Down syndrome was 8.3/10,000. Other published population-based rates for this syndrome are higher 19 (12.4–22.2/10,000). Down syndrome can be diagnosed relatively easily prior to birth by measuring alphafetoprotein, human chorionic gonadotropin and unconjugated estriol in fetal serum, detecting a thickened nuchal fold on fetal ultrasound, and by cytogenetic analysis. Thus, it is likely that many fetuses with Down syndrome are aborted electively and that variable abortion rates contribute to the variable prevalence at birth rates. This conclusion is supported by data from the Strasbourg birth defect registry, which reported the low rate of 2.2/10,000 live births in 1998. This rate however became 19.7/10,000 when aborted fetuses were considered 11. The number of Down syndrome fetuses has increased as the mean age of pregnant women has increased 35.

With regard to nervous system defects, the prevalence rate for spina bifida in our population was lower (1.7/10,000) than found in other registries (3.2–5.2/10,000). For hydrocephalus the combined male-female rate was 5.8/10,000 in our registry, and varied from 3.2 to 11.6 in the other population-based registries 23. The reasons for these wide variations in rates for nervous system defects are not known, but it is likely that variations in rates of elective terminations contribute substantially. No cases of anencephalus or encephalocele were found, probably in relation to improved prenatal diagnosis and elective termination. Recent surveillance data on neural tube defects show they are diagnosed prenatally in about 80% of cases 36. In the US, 20–30% of fetuses with neural tube are terminated 37. Folate intake also varies between populations, and lack of this nutrient is known to cause such defects 38.

Facial clefts are a heterogeneous group of easy-to-recognize non-fatal birth defects 39. They are reported as the most common congenital facial abnormalities, with prevalence at birth estimated at 10/10,000 40 and in the range 6–17 per 10,000 Caucasian births, 4/10,000 for African-Americans and 17/10,000 for Japanese 41. Our population-based data for facial cleft (overall birth prevalence 10.8/10,000) are in line with these estimates but considerably lower than those for Georgia, (15.8/10,000) and Finland (24.3/10,000). We found that they were about twice as common in boys than girls, which is consistent with other published data 40. Facial clefts are considered to be etiologically heterogeneous. A small proportion occur as a part of recognizable pattern of malformations or have a genetic etiology 42, while epidemiologic data suggest that exogenous factors contribute to these conditions. Maternal factors that have been studied for their influence on cleft risk include smoking, alcohol consumption, medication use, environmental chemicals and nutritional factors, but none appear to explain a significant proportion of the population burden of these anomalies 43. Geographic differences in birth prevalence for these anomalies probably reflect differences in maternal life style and exposure to environmental causative factors.

The birth prevalence for esophageal atresia (4.2/10,000) was similar in our study to that reported in Finland (3.3/10,000), whereas that of small intestine atresia was higher (1.7/10,000) in our population than in the Finnish (0.7/10,000). Prevalence in Georgia, (1968 to 1989) has been reported as 2.8/10,000 overall, but higher in black infants (3.7/10,000) 44.

Hirschprung's disease is relatively easy to diagnose, so higher birth prevalence in our population (3.3/10,000) compared to Georgia's (2.1/10,000) and Hawaii's (2.2/10,000) is probably due to genuinely higher birth prevalence of this defect in our population. Although this disease is inherited, environmental factors may be responsible for sporadic cases 45.

The birth prevalences of unilateral and bilateral renal agenesis have been reported at 10/10,000 and 2.5/10,000 respectively 46. At the same time, a study on the epidemiology of kidney malformations reported marked variations in the birth prevalence of renal agenesis (0.6–29 per 10,000), which is considered to be mainly due to variations in the diagnostic procedures used 47. Our overall figure (3.3/10, 000) was somewhat lower than the one for Georgia (4.4/10,000), while Finland reports a very low birth prevalence of this condition (0.7/10,000) in relation to a high rate of terminations of pregnancies with it: the rate for these defects increases to 2.43/10,000 when terminations are considered. We had no cases of bladder exstrophy; birth prevalences of this condition were also low in Finland (0.2/10,000) and Georgia (0.1/10,000).

Our study, limited to selected major birth defects, is the first to provide population-based data on the prevalence rates at birth of congenital anomalies in defined populations in north-western Italy.

The methods used for data collection and case generation are proven to be ones that incorporate ample quality checks. Comparison with an independent source (birth certificates) suggests good completeness and quality. However in order to obtain a dataset that is as complete as possible, we plan to start using birth certificates as an additional data source. We expect to begin registering defects in elective terminations in the near future, as many defects are now identified prenatally and the exclusion of aborted cases complicates the identification of environmental factors in the etiology of these conditions 48. As many malformations are compatible with life, particularly with modern treatments and surgical correction, they are not detected by vital registration systems. Mortality data cannot provide reliable indications of birth prevalence of live birth malformations and thus, registries of such malformations are important.

The author(s) declare that they have no competing interests.

G. Tagliabue conceived the study, participated in its design, verified diagnoses and complete case ascertainment, performed the analyses, and drafted the manuscript.

P. Contiero participated in conceiving, designing and analyzing the study, oversaw data collection and record linkage and reviewed the manuscript.

S. Fabiano, A. Maghini, A. Tittarelli performed automated data acquisition and standardization, and executed record linkage between the information sources.

E. Frassoldi, E. Costa, D. Gada abstracted clinical information from clinical records.

D. Vergani, M. Bellotti performed quality checks on the diagnoses generated by the defects registry.

R. Tessandori, S. Pisani, M. Gambino, F. Caramaschi, P. Crosignani performed a critical evaluation of the analysis and of the study design.

All authors have read and approved the final manuscript.