Birth Defect Prevention: Global Issues - WHO Key Points • 65th World Health Assembly Resolution:...

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Lorenzo D. Botto, MDDivision of Medical GeneticsUniversity of Utah, USA

Pierpaolo Mastroiacovo, MDInternational Center on Birth Defects

Rome, Italy

Birth Defect Prevention: Global Issues

WHO, Geneva, 16 January 2012: Hosts, Dr. Mario Merialdi, Dr. JP Pena‐Rosas

International Clearinghouse for Birth Defects Surveillance and Research ICBDSR

WHO Collaborating Center

WHO 2012 ‐ Global issues in Birth Defect Prevention Botto ‐Mastroiacovo | 1

42 Members in 38 Countries, and one Centre (ICBD, Rome)42 Members in 38 Countries, and one Centre (ICBD, Rome)

Utah

Atlanta

Texas California

Canada National

British ColumbiaAlberta

CubaJapan

(China)Russia

Ukraine

Western Europe21 Registries14 Countries

I lIndia

Mexico

Costa Rica

Chile Maule

ECLAMC10 Countries

Western AustraliaVictoria

New Zealand

IranIsrael

Colombia


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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


Key Points





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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 asTo raise awareness of the importance of birth defects as 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 defectsand prevention of major birth defects


The call to action: requests the Director‐General

• To promote the collection of data on the global burden

65th World Health Assembly Resolution

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.


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Birth DefectsBirth Defects3% of all births :3% of all births :

burden of disease is high :burden of disease is high :aand increasing everywhere:nd increasing everywhere:

minimum estimateminimum estimatemortality, morbidity, disability, costmortality, morbidity, disability, costalso middle/low income also middle/low income countriescountries


Global Issues in Birth Defects = Gaps and Opportunities Global Issues in Birth Defects = Gaps and Opportunities

EvaluationEvaluation ::Prevention :Prevention :

Capacity :Capacity :

llimited/no surveillance programsimited/no surveillance programsknown causes not addressedknown causes not addressedlimited training/expertiselimited training/expertise


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Three congenital conditions account for 25% to 60% of under‐5 mortality, and share many risk factors

Congenital conditions: birth defects (malformations, genetic conditions, developmental disabilities of prenatal origin), preterm birth/IUGR, and birth asphyxia

60%140

(%)

hs)

10%

20%

30%

40%

50%

20

40

60

80

100

120

ribution of causes of deaths

r‐5 mortality rate (per 1,000 birth

0%0 Distr

Under

Birth asphyxia Prematurity Birth defects Under‐5 mortality rate

http://apps.who.int/whosis/data/ http://www.who.int/whosis/mort/download/en/index.html


Key Points





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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 | 11

Developmental timing of some birth defects


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Folic acid alone or as a multivitamin prevents over half of neural tube defects

Neural tube defects: from embryology to clinic

N En

glJ Med

341:1509‐1519, 1

999


Preventing congenital conditions: mitigating risk factors and promoting protective factors

“Diabesity” Lifestyle Infections Select medications

Physical activity

Folic acid fortification, supplementationHealthy eating

Physical activity


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Crucial challenge worldwide:reduce child mortality, improve maternal‐child health


Evidence for modifiable risk factors

Folic acid useYes No

Gene variants in folic acid pathway

Biomarkers in folic acid pathway

RCT

CaseControl

Fortification

MTHFR

FolReceptor

etc

Blood folate

B6

Homocysteine

etc

moreclefts

fewerclefts

Different concentration/frequencyin 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






RCT

CaseControl

Fortification

MTHFR

FolReceptor

etc

Blood folate

B6

Homocysteine

etc

moreNTDs

fewerNTDs

Different concentration/frequencyin babies with NTDs vs. controls

SEARO 2011 ‐ Technical Review Clefts, Limbs, Heart Botto | 18

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Red Cell Folate Hi h th 906 l/L

Blood folate and neural tube defect risk

Higher than 906 nmol/L

How much Plasma Folate ? How do you get there ?

Daly LE et al.: Jama 1995; 274:1698‐1702






RCT

CaseControl

Fortification

MTHFR

FolateReceptor

etc

Blood folate

B6

Homocysteine

etc

moreNTDs

fewerNTDs

Different concentration/frequencyin babies with NTDs vs. controls


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Odds ratioCumulative meta-analysis0.1 0.5 1 2 3 5 10

van der Put (1995) ( 55)

677C‐>T variant of MTHFR (folate) gene and neural tube defect risk (patients): cumulative meta‐analysis

( ) ( )Whitehead (1995) ( 137)Papapetrou (1996) ( 178)Ou (1996) ( 219)Mornet (1997) ( 262)BjorkeMonsen (1997) ( 290)van der Put2 (1998) ( 321)Koch (1998) ( 458)Boduroglu (1998) ( 507)Shaw (1998) ( 721)deFranchis (1998) ( 924)Shields (1999) (1195)Christensen (1999) (1251)GarciaFragoso (1999) (1282)Johanning (1999) (1364)Stegmann (1999) (1375)Yu (2000) (1399)Barber (2000) (1423)

C677T MTHFR SNP in NTD-patients and controls (TT vs CC (red) and CT vs CC (green))

Barber (2000) (1423)Volcik (2000) (1657)Richter (2001) (1693)Wenstrom (2001) (1764)Cunha (2002) (1779)Combined TTCT


[Source: Vollset and Botto, 2001]

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:


Fortification with folic acid

No fortification

Planning

Voluntary

Mandatory


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Folic acid reduces the risk of NTD probably down to ~ 0.6 per 1,000 pregnancies

Black vertical line: drop in NTD occurrenceo after FA fortification in 24 areas o after FA supplementation in in 3 RCT and cohort studies

5 0er 1,000

valence of NTD

x 10,000 Dotted blue line: possible threshold of FA‐preventable NTD

5.0

l prevalence of NTD

, p

4.0

3.0

2.0

1 0

Prev

Total 1.0


0

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: NTDsmitigating risk factors and promoting protective factors

“Diabesity” Lifestyle Infections Select medications

Physical activity

Folic acid fortification, supplementationHealthy eating

Physical activity


Neural Tube Defects, Oral Clefts, Heart defects

Neural Tube Defects

OrofacialClefts

Heart Defects

Prevalence 6 to 100 15 (CL/P) – 6 (CPO) 80‐90e a e ce(/10,000)

6 to 00(1 in 1,000)

5 (C / ) 6 (C O)(1 in 700)

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 ++ ++ +++

Surveillance challenges

+/++‐ External‐ Pregnancy terminations

+‐ External

‐Small cleft palate may be missed at

birth

+++‐Internal

‐ Diagnostic delays, classification


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Types of oral clefts

Nat Rev Genet. 2011 March; 12(3): 167–178.


Modifiable risk factors for oral clefts

Exposure Risk Strength of evidence

Gene‐environment interactions

Smoking Increased 30% Strong GSST1, NOS3, IRF6(RR ~ 1.3)

Seizure meds (some) Increased Fairly consistent

Alcohol Increased ? Unclear, ? binge ADH1C

Hyperthermia Increased Inconsistent

Use of multivitamins/folic acid

Decreased ~25% Fairly consistent, mostly MV

IRF6

Folic acid fortification Decreased? Most data negativeFolic acid fortification ecreased? Most data negative

Zinc deficiency Increased ? Few data

Other (low B6, vit A) Increased Fairly consistent, few data


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Smoking and cleftsCL/P

CL/P = cleft lit +/‐ cleft palateCPO = cleft palate only

•Consistent relative risk ~1.3 (30% increased risk)

•In some countries, high ratesof smoking in women of childbearing age

• Attributable fraction (fraction ofCPOcases of clefts due to smoking)can be quite high, in the orderof 20%

P Mossey, J Little et al, Lancet 2009


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% Strong GSST1, NOS3, IRF6(RR ~ 1.3)

Seizure meds (some) Increased Fairly consistent

Alcohol Increased ? Unclear, ? binge ADH1C

Hyperthermia Increased Inconsistent

Use of multivitamins/folic acid

Decreased ~25% Fairly consistent, mostly MV

IRF6

Folic acid fortification Decreased? Most data negativeFolic acid fortification ecreased? Most data negative

Zinc deficiency Increased ? Few data

Other (low B6, vit A) Increased Fairly consistent, few data


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 i C d Chilbut not in Canada or Chile.

• 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 folatestatus) 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 NetherlandsZinc: 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 orofacialclefts, with a dose‐response relation


Congenital heart defects: common, high impact, costly, heterogeneous

Atrial septal defectsVentricular septal defects(several types)

Tetralogy of FallotD-Transposition of the GATruncus arteriosusInterrupted ao arch type B

Hypoplastic left heart s.Aortic stenosisCoarctation of the aortaCoarctation of the aorta

Pulmonary atresia/intact septumPulmonic stenosis

Complex heterotaxy/laterality defects


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Some known risk factors for CHD

Risk CHD types RR Exposure Etiologic factor prevalence

%fraction

%

Diabetes pregest.

most ~4 to 20 3%

6%

8.3

15

Meds various ~4 1 3Meds various 4 1 3

PKU* LVOTO, Conotr.

>6* < 0.01 0.5

* If uncontrolled mat PHE levelsWHO 2012 ‐ Global issues in Birth Defect Prevention Botto ‐Mastroiacovo | 37

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

13WHO 2012 ‐ Global issues in Birth Defect Prevention Botto ‐Mastroiacovo | 38

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Folic acid or multivitamins and congenital heart defects

Supplementation (MV/FA) Fortification (FA)


Do folic acid supplements influence fever risk ? Trend for lower “fever‐associated” risk among peri‐conceptional supplement users


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Summary

1. 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).

2. 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)


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 4 to 20

– Phenylketonuria (uncontrolled) > 6

• Medications

– Antiepileptic medications ~4

– Thalidomide very high

– Retinoic acid very high


















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Focus on reducing population impact: even ‘weak’ risk factors can have large effects


Estimates of etiologic fractions for some risk factors for heart defects

Risk CHD types Relative Exposure Etiologic factor

ypRisk

pprevalence

%

gfraction

%

PKU* Left Obstr. Conotrunc.

>6* < 0.01 0.5

Meds Various ~4 1 3

Diabetes pregest.

Most ~4 3%

6%

8.3

15

* If uncontrolled mat PHE levelsSEARO 2011 ‐ Strategies for Birth Defect Prevention Botto | 48

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Multiple risks associated with selected modifiable risk factors

Risk factor Other adverse outcomes Exposure lprevalence %

Diabetes, pregest.

Many birth defects, prematurity, infant deaths

3%

6%

PKU* Mental retardation, microcephaly, heart

< 0.01

defects

Seizure meds

Spina bifida, oral clefts, others

1

SEARO 2011 | 50

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Risk factor Other adverse outcomes

Exposure prevalence %

Multiple risks associated with selected modifiable risk factors

outcomes prevalence %

Fever Spina bifida, heart def., prematurity

5‐10%

Smoking Clefts, IUGR/low birth weight, etc

10‐15 %

or more

No folic acid use before conception

Spina bifida, anencephaly, probably others (clefts, heart?)

>50% or more


Approach to primary prevention and health promotion for birth defects

Factor Causes NTDs

Relative

Risk

Common Exposure

Additional Prevention

Non use of folic acid, multivitamin

Definite ++ +++++

(>50%)

Probable

(some clefts, ?CHD)

Diabetes (pregest.) Definite +++ +++

(1‐6%)

Definite

(many birth defects, other)

Select medications 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, SESPerson: 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

















SEARO 2011 | 54

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Planning health interventions: quantity, intensity, equality

Quantity IntensityQuantity

Equality

Intensity

Quantity: population impact, people who benefit from the interventionIntensity: effort to provide benefit, over time Equality : just distribution of benefit, without disparities


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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InfectionsInfections

Preve

immunizatio

ns

ntio

n, Screen

ing, treatm

eent



Smoking

Taxquittin

gxatio

n


30


InfectionsInfections

screen

Immunizatio

ns

ning

School, ccro

wding, h

ygiene



Diabetes

Food, w

screening

weigh

t, activity


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Folic acid

Supple

Fortificatio

ementatio

n

on


The Health Impact Pyramid: quantity, intensity, equality

Quantity Intensity

Equality

Quantity: people who benefit from the value of the interventionIntensity: effort to provide benefit, over time Equality : just distribution of benefit, without disparities


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Key Points


• Modifiable risk factors: what can be done now that can work?

• Global opportunities: prevention, training, surveillanceGlobal opportunities: prevention, training, surveillance


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

• Collaboration International Clearinghouse, WHO, CDCg , ,

• First course 2011, planning 2012


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Training Program onTraining Program onSurveillance 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, Switzerland3 to 6 October 2011


Public Health Surveillance: what health events?

S illSurveillance

Risk factors

(folic acid use, folate levels,

etc)

Outcomes

(morbidity, mortality, cost,

disability)

SEARO 2011 | 66

Occurrence

(prevalence of neural tube defects)

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‐ PoliciesPrevention Surveillance

Enhancing surveillance to include risk factors

‐ Birth defects‐ Preterm births‐ Low birth weight/IUGR‐ Stillbirth‐ Intellectual disability

‐ Folic acid (lack of use)‐ Infections (toxo, rubella, etc)‐Medications (retinoids, VPA)‐ SmokingDiabetes obesity

Policies‐ Interventions

Global burden of risk factors Global burden of disease

1. Three R’s: need for data that are reliable, relevant, recent

2. PAT: Need for Priorities, Approach, Teams optimized to local setting

Intellectual disability‐ …

‐ Diabetes, obesity‐ …


Surveillance of Risk Factors: the Awareness ProjectCollaboration of ICBDSR, CDC, WHO, MOD

Risk Factor Status

Diabetes , pregestational Finished

Obesity, high body mass index To be startedy, g y

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 StartedSmoking Started

Alcohol To be started

Rubella (seronegativity) Updated 2011

Toxoplasmosis (seronegativity) Updated 2011

Varicella (seronegativity) Finished


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Key Points


• Modifiable risk factors: what can be done now that can work?

• Global opportunities: prevention, training, surveillanceGlobal opportunities: prevention, training, surveillance

• DISCUSSION


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