Birth Defect Prevention: Global Issues
Lorenzo D. Botto, MD
Pierpaolo Mastroiacovo, MD
Division of Medical Genetics
University of Utah, USA International Center on Birth Defects
Rome, Italy International Clearinghouse for Birth Defects Surveillance and Research ICBDSR
WHO Collaborating Center
WHO, Geneva, 16 January 2012: Hosts, Dr. Mario Merialdi, Dr. JP Pena‐Rosas
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42 Members in 38 Countries, and one Centre (ICBD, Rome)
Canada Utah
National
British Columbia
Alberta
Western Europe
21 Registries
14 Countries
Ukraine
Russia (China)
Atlanta Texas California
Japan
Cuba
I
Israel
l
Mexico
India
Iran
Costa Rica
Colombia
Chile Maule
ECLAMC
10 Countries
Western Australia
Victoria WHO 2012 ‐ Global issues in Birth Defect Prevention New Zealand
Botto ‐ Mastroiacovo
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Key Points
• 65th World Health Assembly Resolution: call to global action for birth defect surveillance, treatment, prevention
• Modifiable risk factors: what can we do now that works? • Global opportunities: surveillance, training, prevention
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Key Points
• 65th World Health Assembly Resolution: call to global action for birth defect surveillance, treatment, prevention
• Modifiable risk factors: what can we do now that works? • Global opportunities: surveillance, training, prevention
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65th World Health Assembly Resolution
The call to action: urges Member States
To raise awareness of the importance of birth defects as awareness of the importance of birth defects as
• To raise
cause of child morbidity and mortality
• To develop and strengthen registration and surveillance of birth defects
• To strengthen research and studies on etiology, diagnosis and prevention of major birth defects
and prevention
of major birth defects
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65th World Health Assembly Resolution
The call to action: requests the Director‐General
• To promote the collection of data on the global burden of mortality and morbidity due to birth defects
• To continue to collaborate with the ICBDSR to improve collection of data on birth defects
• To support Member States in developing national plans for implementation of effective interventions to prevent and manage birth defects. WHO 2012 ‐ Global issues in Birth Defect Prevention Botto ‐ Mastroiacovo
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Birth Defects
3% of all births : minimum estimate
burden of disease is high : mortality, morbidity, disability, cost
and increasing everywhere: also middle/low income countries
also middle/low income countries
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Global Issues in Birth Defects = Gaps and Opportunities Evaluation : limited/no surveillance programs
Prevention : known causes not addressed
Capacity : limited training/expertise
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Three congenital conditions account for 25% to 60% of under‐5 mortality, and share many risk factors
140
60%
120
50%
100
40%
80
30%
60
20%
40
10%
20
0
0%
Birth asphyxia
http://apps.who.int/whosis/data/
Prematurity
Birth defects
Distrribution of causes of deaths (%)
Underr‐5 mortality rate (per 1,000 birth
hs)
Congenital conditions: birth defects (malformations, genetic conditions, developmental disabilities of prenatal origin), preterm birth/IUGR, and birth asphyxia
Under‐5 mortality rate
http://www.who.int/whosis/mort/download/en/index.html
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Key Points
• 65th World Health Assembly Resolution: call to global action for birth defect surveillance, treatment, prevention
• Modifiable risk factors: what can we do now that works? • Global opportunities: surveillance, training, prevention
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Four Pillars of Effective Prevention LD Botto, Moss and Adams 8th Ed, 2012 in press SEARO 2011 ‐ Strategies for Birth Defect Prevention Botto
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Developmental timing of some birth defects
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Neural tube defects: from embryology to clinic
Folic acid alone or as a multivitamin
prevents over half of neural tube defects
N Engl J Med 341:1509‐1519, 1999
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Preventing congenital conditions: mitigating risk factors and promoting protective factors
“Diabesity”
Lifestyle Infections
Select medications
Physical activity
Physical activity
Healthy eating
Folic acid fortification, supplementation
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Crucial challenge worldwide:
reduce child mortality, improve maternal‐child health
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Evidence for modifiable risk factors
Folic acid use
Yes No
Blood folate
RCT
Case
Control
Fortification
fewer
clefts
Biomarkers in folic acid pathway
more
clefts
B6
Homocysteine
etc
Gene variants in folic acid pathway
MTHFR
Fol
Receptor
etc
Different concentration/frequency
in babies with clefts vs. controls
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Risk of Neural‐Tube Defects and the Use of Folic Acid or Multivitamin Supplements, 1981 through 1999
Source: Botto L et al. N Engl J Med 1999;341:1509‐1519
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Evidence for modifiable risk factors
Folic acid use
Yes No
Blood folate
RCT
B6
Case
Control
Homocysteine
Fortification
fewer
NTDs
Biomarkers in folic acid pathway
more
NTDs
etc
Gene variants in folic acid pathway
MTHFR
Fol
Receptor
etc
Different concentration/frequency
in babies with NTDs vs. controls
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9
Blood folate and neural tube defect risk Red Cell Folate Higher than 906 nmol/L
Hi
h th 906
l/L
How much Plasma Folate ? How do you get there ? Daly LE et al.: Jama 1995; 274:1698‐1702
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Evidence for modifiable risk factors
Folic acid use
Yes No
Blood folate
RCT
B6
Case
Control
Homocysteine
Fortification
fewer
NTDs
Biomarkers in folic acid pathway
more
NTDs
etc
Gene variants in folic acid pathway
MTHFR
Folate
Receptor
etc
Different concentration/frequency
in babies with NTDs vs. controls
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677C‐>T variant of MTHFR (folate) gene and neural tube defect risk (patients): cumulative meta‐analysis
Cumulative meta-analysis
Odds ratio
0.1
van der Put
Whitehead
Papapetrou
Ou
Mornet
BjorkeMonsen
van der Put2
Koch
Boduroglu
Shaw
deFranchis
Shields
Christensen
GarciaFragoso
Johanning
Stegmann
Yu
Barber
Volcik
Richter
Wenstrom
Cunha
Combined
((1995))
(1995)
(1996)
(1996)
(1997)
(1997)
(1998)
(1998)
(1998)
(1998)
(1998)
(1999)
(1999)
(1999)
(1999)
(1999)
(2000)
(2000)
(2000)
(2001)
(2001)
(2002)
0.5
1
2
3
5
10
( 55))
( 137)
( 178)
( 219)
( 262)
( 290)
( 321)
( 458)
( 507)
( 721)
( 924)
(1195)
(1251)
(1282)
(1364)
(1375)
(1399)
(1423)
(1657)
(1693)
(1764)
(1779)
CT
TT
C677T MTHFR SNP in NTD-patients and controls (TT vs CC (red) and CT vs CC (green))
[Source: Vollset and Botto, 2001]
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Recommendations for folic acid supplementation had limited or no effect in Europe
BMJ 2005;330:
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Estimated number of pregnancies with neural tube defects preventable by folic acid in study area, 1993‐8. Estimates assume three scenarios of effectiveness (30%, 60%, 90%), which encompass a reasonable range from low dose fortification to highly effective supplementation
Source: BMJ 2005;330:
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Fortification with folic acid No fortification
Planning
Voluntary
Mandatory
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Folic acid reduces the risk of NTD Prevvalence of NTD x 10,000 Total
l prevalence of NTD, per 1,000
probably down to ~ 0.6 per 1,000 pregnancies
50
5.0
4.0
Black vertical line: drop in NTD occurrence
o after FA fortification in 24 areas o after FA supplementation in in 3 RCT and cohort studies Dotted blue line: possible threshold of FA‐preventable NTD 3.0
2.0
10
1.0
0
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Neural tube defect rates per 10,000 population, by race/ethnicity and fortification period status ‐‐‐
National Birth Defects Prevention Network,* 1995—2007 (MMWR August 13, 2010 / 59(31);980‐984)
Source: BMJ 2005;330:
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Preventing congenital conditions: NTDs
mitigating risk factors and promoting protective factors
“Diabesity”
Lifestyle Infections
Select medications
Physical activity
Physical activity
Healthy eating
Folic acid fortification, supplementation
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Neural Tube Defects, Oral Clefts, Heart defects
Neural Tube Defects
Orofacial
Clefts
Heart Defects
6 to 100
6
to 00
(1 in 1,000)
15 (CL/P) –
5 (C / ) 6 (C
(CPO)
O)
(1 in 700)
80‐90
80
90
(1 in 110)
Rate variations
+++
++
+/‐
Key subtypes
>3
>2
>12
Coding ICD‐10
Adequate
Adequate
Challenging for several types
Photographs
+++
++
‐ (echocardio)
Clinical review
++
++
+++
+/++
‐ External
‐ Pregnancy terminations
+
‐ External
‐Small cleft palate may be missed at birth
+++
‐Internal
‐ Diagnostic delays, classification
Prevalence e a e ce
(/10,000)
Surveillance challenges
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Types of oral clefts
Nat Rev Genet. 2011 March; 12(3): 167–178.
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Modifiable risk factors for oral clefts
Exposure
Risk
Strength of evidence
Gene‐environment interactions
Smoking
Increased 30%
(RR ~ 1.3) Strong
GSST1, NOS3, IRF6
Seizure meds (some)
Increased
Fairly consistent
Alcohol
Increased ?
Unclear, ? binge
Hyperthermia
Increased
Inconsistent Use of Decreased ~25% Fairly consistent, multivitamins/folic acid mostly MV
Folic acid fortification
Folic
acid fortification
Decreased?
ecreased?
Most data
data negative
negative
Zinc deficiency
Increased ?
Few data
Other (low B6, vit A)
Increased
Fairly consistent, few data
WHO 2012 ‐ Global issues in Birth Defect Prevention ADH1C
IRF6
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CL/P
Smoking and clefts
CL/P = cleft lit +/‐ cleft palate
CPO = cleft palate only
•Consistent relative risk ~1.3 (30% increased risk)
•In some countries, high rates
of smoking in women of childbearing age
CPO
• Attributable fraction (fraction of
cases of clefts due to smoking)
can be quite high, in the order
of 20% P Mossey, J Little et al, Lancet 2009
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Estimated fraction of affected babies due to maternal risk factors, by relative risk and exposure frequency in population
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Modifiable risk factors for oral clefts
Exposure
Risk
Strength of evidence
Gene‐environment interactions
Smoking
Increased 30%
(RR ~ 1.3) Strong
GSST1, NOS3, IRF6
Seizure meds (some)
Increased
Fairly consistent
Alcohol
Increased ?
Unclear, ? binge
Hyperthermia
Increased
Inconsistent Use of Decreased ~25% Fairly consistent, multivitamins/folic acid mostly MV
Folic acid fortification
Folic
acid fortification
Decreased?
ecreased?
Zinc deficiency
Increased ?
Few data
Other (low B6, vit A)
Increased
Fairly consistent, few data
ADH1C
IRF6
Most data
data negative
negative
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Clefts, folic acid, multivitamins: part 1
• Folate deficiency causes clefts in animals
• Folate antagonists (meds) associated with increased risk of OFC • Hungarian RCT: too small, ‘controls’ took trace elements (incl. Zn)
• Inconsistent findings in case‐control studies of MV with folic acid, maternal dietary folate intake, and red cell and plasma folate
• Fortification: North America, ?small decline in CL/P, not so in Australia (voluntary). For all clefts combined, small decrease in US b
but not in Canada or Chile.
i C d
Chil
• Open questions: high dose vs. low dose, MV vs. folic acid, recurrence vs. occurrence, population susceptibility
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Clefts, micronutrients: part 2
• Riboflavin and vitamin A: few data
• Homocysteine: increased [hcy] (determined partly by folate
status) in mothers of infants with CL, CLP, CPO
)
,
,
• B6: biomarkers of poor vitamin B6 status associated with increased risk of orofacial clefts in the Netherlands and Philippines. Also, B6 deficiency seen in populations with high intakes of polished rice in Asia, and these groups also seem to have high rates of CL, CLP, CPO
• Zinc: deficiency causes CPO in animals. In the Netherlands Zinc: deficiency causes CPO in animals In the Netherlands
Children with CL, CLP, CPO and their mothers had lower [Zinc] in erythrocytes. In the Philippines, widespread zinc deficiency ; and high maternal zinc in plasma associated with low risk of orofacial
clefts, with a dose‐response relation
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Congenital heart defects: common, high impact, costly, heterogeneous Atrial septal defects
Ventricular septal defects
(several types)
Tetralogy of Fallot
D-Transposition of the GA
Truncus arteriosus
Interrupted ao arch type B
Hypoplastic left heart s.
Aortic stenosis
Coarctation of the aorta
Pulmonary atresia/intact septum
Pulmonic stenosis
Complex heterotaxy/laterality defects
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Some known risk factors for CHD
Risk factor
CHD types
Diabetes most
pregest.
RR
Exposure prevalence %
Etiologic fraction
%
~4 to 20
3%
6%
8.3
15
Meds
various
~4
4
1
3
PKU*
LVOTO, Conotr.
>6*
< 0.01 0.5
* If uncontrolled mat PHE levels
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Possible risk factors for CHD suggestive but not conclusive (>2 studies, mixed)
Factor
CHD types
Relative Risk
Exposure prev., %
Etiologic fract., %
Non use of folic acid, multivitamin
Conotr. Septal
2
30
50
23
33
Fever/flu
Septal Tr. Atr.
2
6
8
5.7
7.4
Obesity
Various
1.2
20
30
3.8
5.7
Smoking
Septal
2
11
15
9.9
13
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Folic acid or multivitamins and congenital heart defects
Supplementation (MV/FA)
SEARO 2011 ‐ Technical Review Clefts, Limbs, Heart Fortification (FA)
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Do folic acid supplements influence fever risk ? Trend for lower “fever‐associated” risk among peri‐conceptional supplement users
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Summary
1.
•
•
•
•
2.
Several known modifiable risk factors: folic acid (protective for neural tube defects)
smoking (oral clefts)
smoking (oral clefts)
diabetes (many birth defects, including heart defects)
some medications (valproate‐NTDs; thalidomide ‐limb defects). Evidence for protective effect of folic acid less clear for birth defects other than neural tube defects: clefts > heart defects > limb anomalies
3. Possible reasons ? Study design, classification, genetic factors in different populations, need for higher folic acid dose, need for multivitamin rather than FA alone (‐> implication for fortification)
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Modifiable risk factors for birth defects: what evidence is helpful?
• Strength of evidence
– Multiple studies, different design, consistent findings • Magnitude of risk: – Relative Risk (how many times higher compared to unexposed?), absolute risk (actual chance of birth defect exposed)
– The higher the risk, the higher the number of affected babies
• Frequency of exposure
– How common among women of childbearing age? – The more common, the more potential cases
• Types of birth defects and associated health outcomes
– The more severe, the more concerning
• Range of outcomes
– Potential for preventing other birth defects, pediatric disorders?
• Effectiveness of interventions
– Potential for high impact (fortification vs. supplementation)
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Modifiable risk factors for birth defects: what evidence is helpful?
• Strength of evidence
– Multiple studies, different design, consistent findings • Magnitude of risk: – Relative Risk (how many times higher compared to unexposed?), absolute risk (actual chance of birth defect exposed)
– The higher the risk, the higher the number of affected babies
• Frequency of exposure
– How common among women of childbearing age? – The more common, the more potential cases
• Types of birth defects and associated health outcomes
– The more severe, the more concerning
• Range of outcomes
– Potential for preventing other birth defects, pediatric disorders?
• Effectiveness of interventions
– Potential for high impact (fortification vs. supplementation)
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Folic acid/vitamin supplementation and congenital heart defects
• Relative Risk < 1 = reduced risk
• Relative Risk > 1 = increased risk
• Confidence interval • Multiple studies
• Different countries
• Different study design
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Modifiable risk factors for congenital heart defects: multiples studies, consistent findings
Relative Risk (range)
Relative Risk (range)
• Maternal conditions
– Diabetes, pregestational
– Phenylketonuria (uncontrolled)
• Medications
– Antiepileptic medications – Thalidomide – Retinoic acid 4 to 20
> 6
~4 very high
very high
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Botto
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Modifiable risk factors for birth defects: what evidence is helpful?
• Strength of evidence
– Multiple studies, different design, consistent findings • Magnitude of risk: – Relative Risk (how many times higher compared to unexposed?), absolute risk (actual chance of birth defect exposed)
– The higher the risk, the higher the number of affected babies
• Frequency of exposure
– How common among women of childbearing age? – The more common, the more potential cases
• Types of birth defects and associated health outcomes
– The more severe, the more concerning
• Range of outcomes
– Potential for preventing other birth defects, pediatric disorders?
• Effectiveness of interventions
– Potential for high impact (fortification vs. supplementation)
SEARO 2011 ‐ Strategies for Birth Defect Prevention 23
Focus on reducing population impact: even ‘weak’ risk factors can have large effects
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Estimates of etiologic fractions for some risk factors for heart defects
Risk factor
CHD types
yp
PKU*
Left Obstr. Conotrunc.
>6*
< 0.01 0.5
Meds
Various
~4
1
3
~4
3%
6%
8.3
15
Diabetes Most
pregest.
Relative Exposure p
Risk
prevalence %
Etiologic g
fraction
%
* If uncontrolled mat PHE levels
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Modifiable risk factors for birth defects: what evidence is helpful?
• Strength of evidence
– Multiple studies, different design, consistent findings • Magnitude of risk: – Relative Risk (how many times higher compared to unexposed?), absolute risk (actual chance of birth defect exposed)
– The higher the risk, the higher the number of affected babies
• Frequency of exposure
– How common among women of childbearing age? – The more common, the more potential cases
• Types of birth defects and associated health outcomes
– The more severe, the more concerning
• Range of outcomes
– Potential for preventing other birth defects, pediatric disorders?
• Effectiveness of interventions
– Potential for high impact (fortification vs. supplementation)
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Multiple risks associated with selected modifiable risk factors
Risk factor
Other adverse outcomes
Exposure prevalence %
l
Diabetes, pregest.
Many birth defects, prematurity, infant deaths
3%
6%
< 0.01 PKU*
Seizure meds
Mental retardation, microcephaly, heart defects
Spina bifida, oral clefts, others
SEARO 2011 1
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Multiple risks associated with selected modifiable risk factors
Risk factor
Fever
Smoking
Other adverse outcomes
Exposure prevalence %
prevalence %
Spina bifida, heart def., prematurity
Clefts, IUGR/low birth weight, etc
5‐10% No folic acid use Spina bifida, before anencephaly, probably conception
others (clefts, heart?)
10‐15 % or more
>50% or more
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Approach to primary prevention and health promotion for birth defects
Factor
Causes NTDs
Non use of folic acid, multivitamin
Definite
Diabetes (pregest.)
Definite
Select medications
Definite
Relative Common Exposure
Risk
++
+++
Additional Prevention
+++++ (>50%)
(some clefts, ?CHD)
+++
(1‐6%)
(many birth defects, other)
++
+
Probable
Definite Definite (NTD, clefts, other)
(NTD, clefts, other)
Fever/flu
Probable
++
+++
(6‐10%)
Possible (CHD)
Smoking
Possible
++
+++
(10‐20%)
Definite (clefts, preterm/IUGR)
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Modifiers of risk may cluster and interact
• Clustering
– Person: smoking, obesity, diabetes, poor nutrition, SES
Person: smoking, obesity, diabetes, poor nutrition, SES
– Place: occupational exposures, residential proximity to waste sites, contaminated water supply
• Interaction
– Exposures could augment the combined birth defect risk
– Alternatively, one could mitigate the other: fever and multivitamin use?
• Need for a global approach, focused on people
– People (not only exposures), baby (not only heart)
• Effective high‐impact interventions, population‐wide
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Modifiable risk factors for birth defects: what evidence is helpful?
• Strength of evidence
– Multiple studies, different design, consistent findings • Magnitude of risk: – Relative Risk (how many times higher compared to unexposed?), absolute risk (actual chance of birth defect exposed)
– The higher the risk, the higher the number of affected babies
• Frequency of exposure
– How common among women of childbearing age? – The more common, the more potential cases
• Types of birth defects and associated health outcomes
– The more severe, the more concerning
• Range of outcomes
– Potential for preventing other birth defects, pediatric disorders?
• Effectiveness of interventions
– Potential for high impact (fortification vs. supplementation)
SEARO 2011 | 54
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Planning health interventions: quantity, intensity, equality
Quantity
Intensity
Equality
Quantity: Intensity:
Equality : population impact, people who benefit from the intervention
effort to provide benefit, over time just distribution of benefit, without disparities SEARO 2011 ‐ Strategies for Birth Defect Prevention Botto
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The Health Impact Pyramid
Frieden TR. A framework for public health action: the health impact pyramid. Am J Public Health 2010;100(4):590-5.
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The Health Impact Pyramid
Infections
Botto
Prevention, Screening, treatmeent
immunizations
SEARO 2011 ‐ Strategies for Birth Defect Prevention | 57
The Health Impact Pyramid
Smoking
quitting
Taxxation
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The Health Impact Pyramid
Infections
screen
ning
Immunizations
School, ccrowding, hygiene
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The Health Impact Pyramid
Diabetes
screening
Food, w
weight, activity
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The Health Impact Pyramid
Folic acid
Supple
ementation
Fortificatio
on
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The Health Impact Pyramid: quantity, intensity, equality
Quantity
Intensity
Equality
Quantity: Intensity:
Equality : people who benefit from the value of the intervention
effort to provide benefit, over time just distribution of benefit, without disparities SEARO 2011 ‐ Strategies for Birth Defect Prevention Botto
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Key Points
• 65th World Health Assembly Resolution: call to global action for birth defect surveillance, treatment, prevention
• Modifiable risk factors: what can be done now that can work? • Global opportunities: prevention, training, surveillance Global opportunities: prevention, training, surveillance
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Global Opportunities: Training Program
• Focuses on prevention and surveillance
– Public health surveillance as a tool for prevention
– Generates baseline, evaluates prevention interventions – Do interventions work, do they change baselines and trends ?
•
•
•
•
Hands‐on, emphasis on small group activities
24 trainees, selected from low‐middle income countries
g
,
,
Collaboration International Clearinghouse, WHO, CDC
First course 2011, planning 2012
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Training Program on
Training
Program on
Surveillance and Prevention of Birth Defects and Preterm Births
International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR)
Centers for Disease Control and Prevention (CDC)
World Health Organization (WHO)
Geneve, Switzerland
3 to 6 October 2011
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Public Health Surveillance: what health events?
S
Surveillance
ill
Risk factors
Outcomes
(folic acid use, folate levels, etc)
(morbidity, mortality, cost, disability)
Occurrence
(prevalence of neural tube defects) SEARO 2011 | 66
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Enhancing surveillance to include risk factors
Surveillance
Prevention ‐ Policies
‐ Interventions
Global burden of risk factors
‐ Folic acid (lack of use)
‐ Infections (toxo, rubella, etc)
‐ Medications (retinoids, VPA)
‐ Smoking
Diabetes obesity
‐ Diabetes, obesity
‐ … Global burden of disease
‐ Birth defects
‐ Preterm births
‐ Low birth weight/IUGR
‐ Stillbirth
‐ Intellectual disability
Intellectual disability
‐ … 1. Three R’s: need for data that are reliable, relevant, recent
2. PAT: Need for Priorities, Approach, Teams optimized to local setting
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Surveillance of Risk Factors: the Awareness Project
Collaboration of ICBDSR, CDC, WHO, MOD
Risk Factor
Status
Diabetes , pregestational
Finished
y, high body mass index
g
y
Obesity,
To be started
Folic acid supplement use
Updated 2011
Folic acid recommendations, policies
Updated 2011
Blood folate status (low)
Advanced
Medications (potentially teratogenic)
Advanced
Pregnancy unplanned or mis‐timed
Started
Smoking
Started
Alcohol
To be started
Rubella (seronegativity)
Updated 2011
Toxoplasmosis (seronegativity)
Updated 2011
Varicella (seronegativity)
Finished
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Key Points
• 65th World Health Assembly Resolution: call to global action for birth defect surveillance, treatment, prevention
• Modifiable risk factors: what can be done now that can work? • Global opportunities: prevention, training, surveillance Global opportunities: prevention, training, surveillance
• DISCUSSION
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