ICBDSR Report 2024

Italy Lombardy CMRL, 2015 to 2017

total births in the 3-year period: 12,114 (livebirths: 12,074)
average births per year: 4,040 (livebirths: 4,020)
terminations of pregnancy legal in country: Yes
data include terminations of pregnancy: Yes
source structure: Population-based

A word from the program about the program

The CMRL program covers part of the Lombardy region in Northern Italy, and includes the Provinces of Sondrio, Varese and the northern part of Milan (HLA1). The program covers about 18.2% of teh annual births in Lombardy, and the 3.1% of births in Italy.
The program obtains electronic data from multiple data systems, including hospital discharge data, death certificates, pathology reports, birth certificates, and social security insurance files. The program uses computer algorithms to identify potential cases. These cases are then evaluated manually to extract and summarize clinical information, which is then coded.The data are interrogated every year to incorporate any new follow up information.
The program includes spontaneous abortion, ectopic pregnancy and placental pathology, for broad inclusion of adverse reproductive outcomes. The program has access to pathology department data for the evaluation of stillbirths, abortions, and fetal autopsies. For renal anomalies, unilateral renal agenesias and severe renal hypoplasia are recorded and coded in detail so that these subgroups can be readily identified in the analysis.

Selected data highlights

Programs share aggregated information on selected major congenital anomalies for joint monitoring and evaluation. Programs may include additional anomalies in their activities. The following tables highlight key findings on the congenital anomalies selected for joint monitoring.

Top Ten by Frequency

Because of their frequency, these conditions impact the largest number of individuals and their families and are the most likely to be encountered in clinical practice. These top ten conditions are selected among those with significant clinical and public health impact. Ffor example, undescended testis is not included in this list.

Condition	Cases	Yearly Avg	Prevalence
Top 10 Conditions by Frequency
among specific diagnoses with major health impact, Italy Lombardy CMRL, 2015-2017 shown are total cases for the reporting period, yearly average cases, and prevalence per 10,000
Down syndrome	58	19	47.9
Hypospadias	56	19	46.2
Limb deficiency, total	25	8	20.6
Neural tube defects, total	14	5	11.6
Hydrocephaly	12	4	9.9
Cleft palate without cleft lip	9	3	7.4
Anencephaly	8	3	6.6
Transposition of great vessels	8	3	6.6
Small intestinal atresia/stenosis	8	3	6.6
Trisomy 18	8	3	6.6
Note: not considered here are microcephaly, undescended testis, and unspecified conditions. However, microcephaly and undescended testis are included in the full table below. The green bar visually compares the prevalence (rows) relative to the most common condition in the table.

Notable Seven

These conditions were selected based on prior knowledge of their overall health impact (morbidity and mortality), regardless of frequency. This selection is the same for all programs. For example, neural tube defects and critical congenital heart disease are included as they may account in some programs for nearly half of all infant deaths associated with congenital anomalies.

Modifiable risk factors are well established for several of these conditions. This implication, as the potential for primary prevention, is unpacked in a later section (‘what if scenario’).

	Yearly cases		Percent liveborn	Prevalence per 10,000
Seven highly impactful conditions
selected on the basis of high morbidity and mortality, and potential for primary prevention Italy Lombardy CMRL, 2015-2017
	Program	Country	Percent liveborn	Prevalence per 10,000
Neural tube defects (NTD)
Neural tube defects, total	5	459	21	11.6
Anencephaly	3	261	12	6.6
Spina bifida	2	162	20	4.1
Orofacial
Cleft palate without cleft lip	3	293	100	7.4
Cleft lip with or without cleft palate	2	162	100	4.1
Heart
Transposition of great vessels	3	261	100	6.6
Tetralogy of Fallot	2	229	57	5.8
Estimated from program prevalence extrapolated to total country births. Italy births for 2022 from World Bank. The green bar visually compares the prevalence (rows) relative to the most common condition in the table.

The full table

This more expansive set of major congenital anomalies, internal and external, includes most conditions of significant clinical and public health impact. Most programs include these conditions, and some even more. Note that a child with multiple anomalies will be counted in all pertinent rows.

A later section provides a more detailed analysis of trisomy 21 (Down syndrome).

	All births			Livebirths
Selected congenital conditions by system
number of cases and prevalence (prev) per 10,000, for all births and livebirths Italy Lombardy CMRL, 2015-2017
	Cases	Prev	95% CI	Cases	Prev	95% CI
Neural tube defects (NTD)
Neural tube defects, total	14	11.6	6.3 - 19.4	3	2.5	0.5 - 7.3
Anencephaly	8	6.6	2.9 - 13.0	1	0.8	0.0 - 4.6
Spina bifida	5	4.1	1.3 - 9.6	1	0.8	0.0 - 4.6
Encephalocele	1	0.8	0.0 - 4.6	1	0.8	0.0 - 4.6
Other brain
Hydrocephaly	12	9.9	5.1 - 17.3	2	1.7	0.2 - 6.0
Microcephaly	10	8.3	4.0 - 15.2	5	4.1	0.5 - 7.8
Holoprosencephaly	6	5.0	1.8 - 10.8	-	-	-
Eye and Ear
Microphthalmos	2	1.7	0.2 - 6.0	2	1.7	0.2 - 6.0
Anophthalmos	-	-	-	-	-	-
Anotia	-	-	-	-	-	-
Microtia	-	-	-	-	-	-
Orofacial
Cleft palate without cleft lip	9	7.4	3.4 - 14.1	9	7.5	2.6 - 12.3
Cleft lip with or without cleft palate	5	4.1	1.3 - 9.6	5	4.1	0.5 - 7.8
Choanal atresia bilateral	-	-	-	-	-	-
Heart
Transposition of great vessels	8	6.6	2.9 - 13.0	8	6.6	2.0 - 11.2
Tetralogy of Fallot	7	5.8	2.3 - 11.9	4	3.3	0.9 - 8.5
Coarctation of aorta	7	5.8	2.3 - 11.9	7	5.8	1.5 - 10.1
Hypoplastic left heart syndrome	-	-	-	-	-	-
Gastrointestinal
Small intestinal atresia/stenosis	8	6.6	2.9 - 13.0	8	6.6	2.0 - 11.2
Esophageal atresia	5	4.1	1.3 - 9.6	4	3.3	0.9 - 8.5
Anorectal atresia/stenosis	5	4.1	1.3 - 9.6	3	2.5	0.5 - 7.3
Genitourinary
Hypospadias	56	46.2	34.9 - 60.0	56	46.4	34.3 - 58.5
Cystic kidney	7	5.8	2.3 - 11.9	5	4.1	0.5 - 7.8
Renal agenesis	6	5.0	1.8 - 10.8	4	3.3	0.9 - 8.5
Indeterminate sex	2	1.7	0.2 - 6.0	2	1.7	0.2 - 6.0
Undescended testis	-	-	-	-	-	-
Epispadias	-	-	-	-	-	-
Bladder exstrophy	-	-	-	-	-	-
Limb
Limb deficiency, total	25	20.6	13.4 - 30.5	16	13.3	6.8 - 19.7
Polydactyly preaxial	-	-	-	-	-	-
Limb deficiency, transverse	-	-	-	-	-	-
Limb deficiency, preaxial	-	-	-	-	-	-
Limb deficiency, postaxial	-	-	-	-	-	-
Limb deficiency, axial	-	-	-	-	-	-
Limb deficiency, intercalary	-	-	-	-	-	-
Limb deficiency, mixed	-	-	-	-	-	-
Abdominal
Omphalocele	4	3.3	0.9 - 8.5	1	0.8	0.0 - 4.6
Gastroschisis	4	3.3	0.9 - 8.5	3	2.5	0.5 - 7.3
Diaphragmatic hernia	3	2.5	0.5 - 7.2	2	1.7	0.2 - 6.0
Prune belly sequence	-	-	-	-	-	-
Chromosomal
Down syndrome	58	47.9	36.4 - 61.9	21	17.4	10.0 - 24.8
Trisomy 18	8	6.6	2.9 - 13.0	-	-	-
Trisomy 13	1	0.8	0.0 - 4.6	1	0.8	0.0 - 4.6
Note a dash (-) indicates data not available or not provided

A deeper look: comments from the program leads

The program leads provide their insights on data, operations, and recent achievements. Their interpretation of the data is particularly valuable because of their local experience and knowledge.

The program includes electronic data from multiple data systems, including hospital discharge data, death certificates, pathology reports, birth certificates, and social security insurance files. The program uses computer algorithms to identify potential cases. These are then evaluated manually to extract and summarize clinical information, which is then coded.
The program includes spontaneous abortion, ectopic pregnancy and placental pathology, for broad inclusin of adverse reproductive outcomes. The program has access to pathology department data for the evaluation of stillbirths, abortions, and fetal autopsies. The data are interrogated every year to incorporate any new follow up information.

For renal anomalies, unilateral renal agenesias and severe renal hypoplasia are recorded and coded in detail so that these subgroups can be readily identified in the analysis.

Down syndrome (trisomy 21)

By far the most common chromosomal anomaly, Down syndrome is known to occur more frequently (has a higher risk of occurrence) in births of women with higher maternal age

This pattern is universally observed, provided there is no significant bias toward missing pregnancies with Down syndrome in older women (e.g., because of unreported pregnancy terminations)

	All cases			Livebirths
Down syndrome, overall and by maternal age
separately for all births and livebirths, prevalence per 10,000 (Poisson exact confidence intervals) Italy Lombardy CMRL, 2015-2017
	Cases	Prev	95% CI	Cases	Prev	95% CI
All maternal ages	58	47.9	36.4 - 61.9	21	17.4	10.0 - 24.8
< 20 years	-	-	-	-	-	-
20 to 24	2	14.2	1.7 - 51.3	2	14.2	1.7 - 51.3
25 to 29	6	16.4	6.0 - 35.6	2	5.5	0.7 - 19.7
30 to 34	7	13.7	5.5 - 28.2	2	3.9	0.5 - 14.1
35 to 39	21	60.6	37.5 - 92.6	7	20.2	5.3 - 35.2
40 to 44	21	213.8	132.4 - 326.9	8	81.5	25.2 - 137.7
45+ years	1	144.9	3.7 - 781.2	-	-	-
Age unspec.	-	-	-	-	-	-
Age unspec. = maternal age unknown or unspecified

Down syndrome - maternal age pyramid

Because of the relation between prevalence of Down syndrome and maternal age, the maternal age distribution in the population is a major determinant of the number of conceptions with Down syndrome in the population.

For programs that have maternal age specific data, one can compare the maternal-age ‘pyramid’ for all births in the population with that of births with Down syndrome. Typically, the distribution is skewed, with a relative excess of births with Down syndrome among the more advanced maternal age groups.

Down syndrome - birth rates matter

Despite the considerably higher risk (rates) of Down syndrome in mothers over 40 or 45 years, these age groups contribute comparatively fewer affected births than younger age groups. This is because birth rates matter: fewer births in the more advanced age groups mean fewer cases overall from those age groups.

A Pareto chart helps highlight the cumulative contribution of different age groups to the total number of cases. This information can help inform strategies for testing and counseling.

Linking risk factor profile and congenital anomalies

The term triple surveillance refers to a model of public health surveillance that births includes the full causal chain, from a) risk factors, which influence the number of affected pregnancies; to b) the affected pregnancies themselves, that are vulnerable to adverse health outcomes; and to c) the health outcomes in affected individuals. The burden of risk becomes expressed eventually in the burden of disease.

Historically, birth defect surveillance has focused on the second element, the occurrence of congenital anomalies.

However, improving outcomes (morbidity, mortality, disability) requires understanding and tracking risk factors (to improve primary prevention) and health outcomes (to improve care). Triple surveillance advocates integrating the tracking of all three elements in this causal chain. Together, these three domains provide clinicians, public health professionals, and policy makers with information to act.

To highlight such context, the next sections provide elements of country demographics, outcomes (mainly early mortality), and selected risk factors. These data, particularly those on risk factors and outcomes, are sometimes directly measured, and sometimes estimated. Birth defect programs with their partners can supplement these data with local assessments.

Country demographics

A surveillance program operates within its country’s demographic situation and trends. This information adds meaning and context to birth defect surveillance information.

Key Indicator	2022 data
Demographic Indicators, Italy
on population, births, life expectancy
Total population	59,013,667
Number of births	395,392
Birth rate (per 1000 pop)	6.7
Fertility (births per woman)	1.2
Life expectancy at birth (years)	82.9
Source: World Bank (accessed Sept 2024)

From program to country

Many (though not all) programs cover a proportion of the country in which they operate. In this setting, a common question is what the program can tell use about the impact of congenital anomalies country-wide, under the assumption that the program information is a good estimator for the country itself. This assumption, of course, needs to be carefully examined, and the program staff typically has the local knowledge to help frame such estimates within the strengths and limitations of the data.

The table below uses the prevalence measured within the program to estimate the number of births with selected congenital anomalies for the entire country. These extrapolations have limitations, and in most cases are illustrative. However, at times a program that covers a proportion of the population may be the only practical window into congenital anomalies country-wide.

	All cases	liveborn
A window into the country: Italy, 2022 estimates
Country-wide estimates for selected conditions (395,392 births), extrapolating from program data
Neural tube defects (NTD)
Neural tube defects, total	457	98
Anencephaly	261	33
Spina bifida	163	33
Encephalocele	33	33
Other brain
Hydrocephaly	392	65
Microcephaly	326	164
Holoprosencephaly	196	-
Eye and Ear
Microphthalmos	65	65
Orofacial
Cleft palate without cleft lip	294	295
Cleft lip with or without cleft palate	163	164
Heart
Transposition of great vessels	261	262
Tetralogy of Fallot	228	131
Coarctation of aorta	228	229
Gastrointestinal
Small intestinal atresia/stenosis	261	262
Esophageal atresia	163	131
Anorectal atresia/stenosis	163	98
Genitourinary
Hypospadias	1828	1834
Cystic kidney	228	164
Renal agenesis	196	131
Indeterminate sex	65	65
Limb
Limb deficiency, total	816	524
Abdominal
Omphalocele	131	33
Gastroschisis	131	98
Diaphragmatic hernia	98	65
Chromosomal
Down syndrome	1893	688
Trisomy 18	261	-
Trisomy 13	33	33
Note: includes conditions with at least 5 estimated cases. Assumes that prevalence estimates from program are valid country-wide.

Outcomes - early mortality

The relative impact of congenital anomalies on early mortality (neonatal, infant, and under 5 years) tends to increase as infant mortality due to other causes falls. This pattern has been observed worldwide. These general indicators of early mortality are tracked regularly by public health agencies.

Key Indicator	2022 data
Mortality Indicators, Italy
Neonatal mortality (per 1000)	1.6
Infant mortality (per 1000)	2.2
Under 5 mortality (per 1000)	2.6
Source: World Bank, accessed Sept 2024. The green bar visually compares the indicators (rows) relative to the indicator with the highest value.

Outcomes - mortality with congenital anomalies

A more specific indicator (infant deaths due to congenital anomalies) is more challenging to document accurately. Missed diagnoses, especially of internal anomalies, can lead to massive underestimates, especially in settings where diagnoses rely only or mostly on an external exam. The table below summarizes data and estimates from systematic public sources. However, local assessments from birth defect surveillance program can help improve the quality of this key indicator.

Age group	Percent	Deaths / 100k pop
Deaths due to birth defects, Italy
among infants (< 1 year old) and from first to fifth birthday
Infants	24.1	62.0
1 to < 5 yrs	13.4	1.5
Source: WHO mortality data for 2020 \| who.int. The green bar visually compares the indicators (rows) relative to the indicator with the highest value.

Risk factors

Some modifiable exposures are well-established risk factors for congenital anomalies. Reducing these exposures is the basis for effective primary prevention. Here we focus specifically on smoking, diabetes, and folate insufficiency. These factors, both common and modifiable, increase the risk of major contributors to morbidity and mortality, including orofacial clefts, neural tube defects, and serious congenital heart disease. The impact of these risk factors depend on their frequency in the population. The following tables show frequency estimates for the country. In another section, these data are used to estimate the number of cases in the country potentially preventable by eliminating the risk factors.

Smoking

Smoking is associated with increased risk for many adverse pregnancy outcomes and several congenital anomalies, including orofacial clefts and probably congenital heart disease. The increased risk is relatively modest (odds ratios tipically less than 1.5) but the effect size, or number of cases due to smoking, depends on the rate of smoking among women who become pregnant. Here we used country-specific estimates of smoking in women of reproductive age (see table for references). Rates of smoking during pregnancy tend to be lower, but by the time many women know they are pregnant, the at-risk period for congenital anomalies has often already passed.

Women	Frequency (%)
Smoking in women
Frequency in two different groups, Italy
Of reproductive age	21.7 ( 18.3 - 25.1 )
During pregnancy	16.1 ( 11.0 - 21.9 )
Source: IHME \| www.healthdata.org \| and Lange 2018

Diabetes

Maternal pregestational diabetes is associated with increased risk for many serious congenital anomalies, including spina bifida, several critical congenital heart defects, and multiple congenital anomalies, among others. In some cases the relative risk (or odds ratio) can be quite high, above 4 or 5 in some cases. The effect size (number of cases due to diabetes) depends on the frequency of diabetes, which tipically increases with age.

Age Group	Percent
Diabetes in women
Frequency by age group, Italy
15 to 19	0.3
20 to 24	0.4
25 to 29	0.5
30 to 34	0.7
35 to 39	1.4
40 to 44	2.6
45 to 49	3.9
Source: IHME \| www.healthdata.org

Folate insufficiency

Folate insufficiency is associated with increased risk for neural tube defects and perhaps other congenital anomalies. On a population-basis, well-implemented folic acid fortification is estimated to decrease the prevalence of neural tube defects below 6 per 10,000 or perhaps even lower. Folic acid fortification is most effective when it is mandatory and universal, meaning that it involves foods commonly consumed by large parts of the population (e.g., wheat, maize, rice, depending on culture and geography).

Mandatory	Food vehicle	Year started
Folic acid fortification
Status of mandatory fortification in Italy
No	-	-
Source: Country program and FFI \| fortificationdata.org

What if - prevention scenarios

What follows is a tricky but important exercise. By combining information about risk factors and prevalence of congenital anomalies, one can attempt to estimate the number of cases attributable to risk factors. This is illustrated in the table below, which uses prevalence information from the program and risk factor information (e.g., diabetes frequency in women) from country data. These estimates also require knowing the relative risk of disease given the exposure. Here we use odds ratios derived from high quality studies and metanalyses. These data then are fed into the Levine estimator of attributable fraction to generate the scenarios that you see in the table. For neural tube defects, we used a different approach. We used 6 per 10,000 as the (conservative) estimate of the birth prevalence achievable by fully implemented folate fortification, and postulated that a prevalence in excess of this value consists of cases attributable to folate insufficiency (as relates to neural tube defect prevention).

	Prevalence per 10,000	attributable cases			Risk factor parameters
Attributable cases for selected risk factors
yearly estimates in program and in country, and per million births Italy Lombardy CMRL, 2015-2017
	Prevalence per 10,000	Program	Country	per 1M births	Risk factor parameters
Neural tube defects (NTD)
Neural tube defects, total	11.6	2	221	560	Presumed folate insufficiency, prevalence > 6
Orofacial
Cleft palate without cleft lip	7.4	0	13	34	smoking, freq: 21.7%, OR: 1.22
Cleft lip with or without cleft palate	4.1	0	11	28	smoking, freq: 21.7%, OR: 1.34
Heart
Transposition of great vessels	6.6	0	3	8	diabetes, freq: 0.5%, OR: 3.34
Tetralogy of Fallot	5.8	0	4	11	diabetes, freq: 0.5%, OR: 4.89
Odds ratios from literature, exposure frequencies from country estimates (see methods for details). Estimates for neural tube defects are provided only when reported prevalence is greater than 6 per 10,000. Note that for programs that do not include stillbirths or terminations of pregnancy, these may be underestimates.

Arguably, these estimates are simplistic. For one, they assume accurate inputs and lack of interactions between risk factors. For neural tube defects, for example, the assumption is that the reported prevalence is accurate (e.g., that it includes stillbirths and pregnancy terminations) and that the excess prevalence is entirely due to (or preventable by) the folate status of the population.

For smoking and diabetes, these estimates assume, for example, that the reported smoking rates in women reflect the smoking rates in the at-risk period, typically the periconceptional period. Smoking rates in pregnancy are typically lower than rates among women of childbearing age, but many women realize they are pregnant after the at-risk period for many congenital anomalies. One may argue that the true smoking rates in the at-risk period are somewhere between these two estimates .

Finally, the computation of attributable cases in these scenarios considers risk factors ‘one at the the time’ and does not account, for example, for multiple exposures (e.g., diabetes and smoking) or interactions among multiple exposures. And so on.

Nevertheless, even rough estimates provide an important message. Some instances, perhaps many, of major and even lethal congenital anomalies are preventable by reducing the burden of risk in populations and individuals. Moreover, for many risk factors (smoking and diabetes in particular), the benefits of exposure mitigation extend beyond the prevention of congenital anomalies to the prevention of many other health conditions, for the fetus as well as for parents.