ICBDSR Report 2024

Italy Campania BDRCam, 2015 to 2017

total births in the 3-year period: 151,828 (livebirths: 151,338)
average births per year: 50,610 (livebirths: 50,450)
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 BDRCam program is population-based and covers 100% of all births, stillbirth and ETOPFA among residents in the Campania region in southern Italy. The program has access to data from the regional birth defect registry (CEDAP) and the hospital discharge data system (SDO). In 2015-2017 we observed an approximately 20% decrease in the number of reported ETOPFA (elective termiations of pregnancies due to fetal anomaly), which we ascribe to decreased notification. Data recovery attempts are in progress.

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 Campania BDRCam, 2015-2017 shown are total cases for the reporting period, yearly average cases, and prevalence per 10,000
Down syndrome	209	70	13.8
Renal agenesis	150	50	9.9
Cleft lip with or without cleft palate	106	35	7.0
Neural tube defects, total	95	32	6.3
Cystic kidney	95	32	6.3
Down s. age unspec.	91	30	6.0
Hydrocephaly	88	29	5.8
Cleft palate without cleft lip	78	26	5.1
Anorectal atresia/stenosis	74	25	4.9
Coarctation of aorta	72	24	4.7
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 Campania BDRCam, 2015-2017
	Program	Country	Percent liveborn	Prevalence per 10,000
Orofacial
Cleft lip with or without cleft palate	35	277	92	7.0
Cleft palate without cleft lip	26	202	99	5.1
Neural tube defects (NTD)
Neural tube defects, total	32	249	37	6.3
Spina bifida	15	119	51	3.0
Anencephaly	12	95	17	2.4
Heart
Tetralogy of Fallot	21	162	84	4.1
Transposition of great vessels	13	99	89	2.5
Hypoplastic left heart syndrome	10	79	45	2.0
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 Campania BDRCam, 2015-2017
	Cases	Prev	95% CI	Cases	Prev	95% CI
Neural tube defects (NTD)
Neural tube defects, total	95	6.3	5.1 - 7.6	35	2.3	1.5 - 3.1
Spina bifida	45	3.0	2.2 - 4.0	23	1.5	0.9 - 2.1
Anencephaly	36	2.4	1.7 - 3.3	6	0.4	0.1 - 0.7
Encephalocele	14	0.9	0.5 - 1.5	6	0.4	0.1 - 0.7
Other brain
Hydrocephaly	88	5.8	4.6 - 7.1	48	3.2	2.3 - 4.1
Microcephaly	25	1.6	1.1 - 2.4	21	1.4	0.8 - 2.0
Holoprosencephaly	16	1.1	0.6 - 1.7	2	0.1	0.0 - 0.5
Eye and Ear
Microphthalmos	9	0.6	0.3 - 1.1	9	0.6	0.2 - 1.0
A/microtia, unspec.	4	0.3	0.1 - 0.7	4	0.3	0.1 - 0.7
Microtia	3	0.2	0.0 - 0.6	3	0.2	0.0 - 0.6
Anophthalmos	2	0.1	0.0 - 0.5	2	0.1	0.0 - 0.5
Anotia	2	0.1	0.0 - 0.5	2	0.1	0.0 - 0.5
Orofacial
Cleft lip with or without cleft palate	106	7.0	5.7 - 8.4	98	6.5	5.2 - 7.8
Cleft palate without cleft lip	78	5.1	4.1 - 6.4	77	5.1	4.0 - 6.2
Choanal atresia bilateral	8	0.5	0.2 - 1.0	6	0.4	0.1 - 0.7
Heart
Coarctation of aorta	72	4.7	3.7 - 6.0	71	4.7	3.6 - 5.8
Tetralogy of Fallot	63	4.1	3.2 - 5.3	53	3.5	2.6 - 4.4
Transposition of great vessels	38	2.5	1.8 - 3.4	34	2.2	1.5 - 3.0
Hypoplastic left heart syndrome	31	2.0	1.4 - 2.9	14	0.9	0.4 - 1.4
Gastrointestinal
Anorectal atresia/stenosis	74	4.9	3.8 - 6.1	70	4.6	3.5 - 5.7
Esophageal atresia	59	3.9	3.0 - 5.0	59	3.9	2.9 - 4.9
Small intestinal atresia/stenosis	41	2.7	1.9 - 3.7	41	2.7	1.9 - 3.5
Genitourinary
Renal agenesis	150	9.9	8.4 - 11.6	137	9.1	7.5 - 10.6
Cystic kidney	95	6.3	5.1 - 7.6	91	6.0	4.8 - 7.2
Hypospadias	15	1.0	0.6 - 1.6	15	1.0	0.5 - 1.5
Indeterminate sex	8	0.5	0.2 - 1.0	4	0.3	0.1 - 0.7
Epispadias	5	0.3	0.1 - 0.8	5	0.3	0.0 - 0.6
Bladder exstrophy	1	0.1	0.0 - 0.4	1	0.1	0.0 - 0.4
Undescended testis	-	-	-	-	-	-
Limb
Limb deficiency, total	69	4.5	3.5 - 5.8	58	3.8	2.8 - 4.8
Limb deficiency, transverse	41	2.7	1.9 - 3.7	38	2.5	1.7 - 3.3
Polydactyly preaxial	18	1.2	0.7 - 1.9	18	1.2	0.6 - 1.7
Limb deficiency, postaxial	7	0.5	0.2 - 0.9	5	0.3	0.0 - 0.6
Limb deficiency, unspec.	7	0.5	0.2 - 0.9	5	0.3	0.0 - 0.6
Limb deficiency, preaxial	5	0.3	0.1 - 0.8	1	0.1	0.0 - 0.4
Limb deficiency, axial	5	0.3	0.1 - 0.8	5	0.3	0.0 - 0.6
Limb deficiency, mixed	3	0.2	0.0 - 0.6	3	0.2	0.0 - 0.6
Limb deficiency, intercalary	1	0.1	0.0 - 0.4	1	0.1	0.0 - 0.4
Abdominal
Diaphragmatic hernia	57	3.8	2.8 - 4.9	45	3.0	2.1 - 3.8
Omphalocele	11	0.7	0.4 - 1.3	3	0.2	0.0 - 0.6
Gastroschisis	3	0.2	0.0 - 0.6	1	0.1	0.0 - 0.4
Prune belly sequence	0	0.0	0.0 - 0.2	0	0.0	0.0 - 0.2
Chromosomal
Down syndrome	209	13.8	12.0 - 15.8	116	7.7	6.3 - 9.1
Trisomy 18	45	3.0	2.2 - 4.0	12	0.8	0.3 - 1.2
Trisomy 13	19	1.3	0.8 - 2.0	5	0.3	0.0 - 0.6
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.

In 2015-2017 we observed an approximately 20% decrease in the number of reported ETOPFA (elective termiations of pregnancies due to fetal anomaly), which we ascribe to decreased notification. Data recovery attempts are in progress. The registry is population-based and covers 100% of all births, stillbirth and ETOPFA among those residing in the region. There is an established link between the regional birth defect registry (CEDAP) and the hospital discharge data system (SDO).

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 Campania BDRCam, 2015-2017
	Cases	Prev	95% CI	Cases	Prev	95% CI
All maternal ages	209	13.8	12.0 - 15.8	116	7.7	6.3 - 9.1
< 20 years	1	3.0	0.1 - 16.7	1	3.0	0.1 - 16.7
20 to 24	0	0.0	0.0 - 2.3	0	0.0	0.0 - 2.3
25 to 29	3	0.8	0.2 - 2.3	1	0.3	0.0 - 1.4
30 to 34	20	3.9	2.4 - 6.0	7	1.4	0.4 - 2.4
35 to 39	41	12.6	9.0 - 17.1	15	4.6	2.3 - 6.9
40 to 44	47	54.3	39.9 - 72.2	7	8.1	2.1 - 14.1
45+ years	6	64.8	23.8 - 141.0	1	10.8	0.3 - 60.0
Age unspec.	91	-	-	84	-	-
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	247	91
Spina bifida	117	60
Anencephaly	94	16
Encephalocele	36	16
Other brain
Hydrocephaly	229	125
Microcephaly	65	55
Holoprosencephaly	42	5
Eye and Ear
Microphthalmos	23	24
A/microtia, unspec.	10	10
Microtia	8	8
Anophthalmos	5	5
Anotia	5	5
Orofacial
Cleft lip with or without cleft palate	276	256
Cleft palate without cleft lip	203	201
Choanal atresia bilateral	21	16
Heart
Coarctation of aorta	188	185
Tetralogy of Fallot	164	138
Transposition of great vessels	99	89
Hypoplastic left heart syndrome	81	37
Gastrointestinal
Anorectal atresia/stenosis	193	183
Esophageal atresia	154	154
Small intestinal atresia/stenosis	107	107
Genitourinary
Renal agenesis	391	358
Cystic kidney	247	238
Hypospadias	39	39
Indeterminate sex	21	10
Epispadias	13	13
Limb
Limb deficiency, total	180	152
Limb deficiency, transverse	107	99
Polydactyly preaxial	47	47
Limb deficiency, postaxial	18	13
Limb deficiency, unspec.	18	13
Limb deficiency, preaxial	13	3
Limb deficiency, axial	13	13
Limb deficiency, mixed	8	8
Abdominal
Diaphragmatic hernia	148	118
Omphalocele	29	8
Gastroschisis	8	3
Chromosomal
Down syndrome	544	303
Trisomy 18	117	31
Trisomy 13	49	13
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 Campania BDRCam, 2015-2017
	Prevalence per 10,000	Program	Country	per 1M births	Risk factor parameters
Orofacial
Cleft lip with or without cleft palate	7.0	2	19	48	smoking, freq: 21.7%, OR: 1.34
Cleft palate without cleft lip	5.1	1	9	23	smoking, freq: 21.7%, OR: 1.22
Neural tube defects (NTD)
Neural tube defects, total	6.3	2	12	30	Presumed folate insufficiency, prevalence > 6
Heart
Tetralogy of Fallot	4.1	0	3	8	diabetes, freq: 0.5%, OR: 4.89
Transposition of great vessels	2.5	0	1	3	diabetes, freq: 0.5%, OR: 3.34
Hypoplastic left heart syndrome	2.0	0	1	4	diabetes, freq: 0.5%, OR: 4.58
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.