Transcript Multi-vitamin Distribution: Legislation, logistics

Folic Acid: Update on the
“Wonder” Drug
36th National Spina Bifida Association Conference
July 2, 2009
Russell S. Kirby, PhD, MS, FACE,
University of South Florida, Tampa, Florida
Julianne S. Collins, PhD
Greenwood Genetic Center, Greenwood, South Carolina
Session Objectives
1. Learn how folic acid consumption can
prevent the recurrence of neural tube
defects
2. Describe how fortification decreases the
mortality and severity of spina bifida
But first, some background
information
Causes of Birth Defects Among Affected Infants
Chromosomal
10%
Single Mutant Genes
and Familial
18%
66%
Unknown
3%
3%
Uterine Factors
Teratogens
From Nelson and Holmes, NEJM January 5, 1989
The Birth Defects Data Dilemma in Visual Form
From: Källén, Epidemiology of Human Reproduction, 1988
Quality of Evidence
I:
Evidence obtained from at least one properly
randomized controlled trial.
II-1: Evidence obtained from well-designed controlled trials
without randomization.
II-2: Evidence obtained from well-designed cohort or casecontrol analytic studies, preferably from more than one
center or research group.
II-3: Evidence obtained from multiple time series with or
without the intervention. Dramatic results in uncontrolled
experiments (i.e. results of introduction of penicillin
treatment in 1940s) could also be regarded as this type of
evidence.
III:
Opinions of well-respected authorities, based on clinical
experience; descriptive studies and case reports; or reports
of expert committees.
Source: Guide to Clinical Preventive Services, Second Edition. Report of the U.S.
Preventive Services Task Force. (Alexandria, VA: International Medical Publishing, 1996.
A PREVENTION
PARABLE
“In theory, there is no difference
between theory and practice. In
practice there is.”
- Yogi Berra
Folic Acid and NTDs
 Smithells et al. 1973: case-control study
showing that periconceptional multivitamins prevent spina bifida
 Numerous other reports over ensuing 18
years
 MRC study published Sept 1991: RCCT
 Hungarian RCCT study shortly thereafter
Folic Acid and NTDs (continued)
 CDC recommendations 1992
 FDA fortifies US food supply with 140 mcg/dl
effective January 1998
 Evidence (Williams et al., Teratology 2002;
Honein et al. JAMA 2001) shows that birth
prevalence of NTDs in US declinined; rates
stabilizing since 2000
 Declines are at the very edge of the range
suggested from the RCCTs (25-30%
compared to anticipated 30-70%)
 Anencephaly decline smaller (~20%)
Folic Acid and NTDs
(continued)
 Is the food supply fortified sufficiently at
the current level?
 How many pregnancies affected by
NTDs might be prevented with higher
levels of fortification?
Folic Acid and NTDs (continued)
 “Current fortification programs are
preventing about 22,000, or 9% of the
estimated folic acid-preventable spina
bifida and anencephaly cases.”
 “This represents an annual global
decrease of about 6,600 folic acidpreventable spina bifida and
anencephaly cases since 2006.”
 Bell and Oakley, 2009. Birth Defects Res A Clin Mol
Teratol 85(1): 102-107.
Folic Acid and NTDs (continued)
 “The
pace of preventing these serious
birth defects can be accelerated if
more countries require fortification of
both wheat and maize flour and if
regulators set fortification levels high
enough to increase a woman's daily
average consumption of folic acid to
400 mcg.”

Bell and Oakley, 2009. Birth Defects Res A Clin
Mol Teratol 85(1): 102-107.
Folic Acid and NTDs (continued)
 Fortification
of corn flour in the US
would increase the consumption of
folic acid by Hispanic women 20%
(Hamner et al. 2009 Am J Clin Nutr
89(1): 305-315)
Epidemiology:
all the world translates into a 2 x 2 table
Disease Outcome
Risk Factor
Yes
Yes
No
No
The interface between health/biomedical
research and public health policy: also a 2 x 2
table?
Political Will
Scientific Evidence
Strong
Weak
Strong
Weak
Based on the ideas of Kay Johnson (1997)
Study Design for first NBDPN
Project
• States with population-based birth defects
surveillance programs invited to participate
• Provided data on numbers of cases and
numbers of birth events by calendar quarter
from Jan 1997 to Dec 1999 (and annually for
1995 and 1996)
• Data grouped by whether the program includes
prenatally ascertained cases
• Parenthetical note: this surveillance process is
ongoing. Initial papers published as Williams LJ
et al., Teratology 2002, and Williams LJ et al.,
Pediatrics 2005.
Prevalence of spina bifida and anencephaly
among all 24 participating surveillance
programs
6.0
Spina bifida
Prevalence (per 10,000)
5.0
Anencephaly
4.0
3.0
2.0
1.0
Pre-fortification
Optional Fortification
Mandatory Fortification
0.0
1995
1996
1997
1998
1999
Year & quarter of birth
2000
2001
Prevalence of spina bifida among
programs with and without prenatal
ascertainment
8.0
Prenatal ascertainment
Prevalence (per 10,000)
7.0
No prenatal ascertainment
6.0
5.0
4.0
3.0
2.0
1.0
0.0
Pre-fortification
1995
1996
Optional Fortification
1997
1998
Year & quarter of birth
Mandatory Fortification
1999
2000
2001
Prevalence of anencephaly among
programs with and without prenatal
ascertainment
Prenatal ascertainment
Prevalence (per 10,000)
No prenatal ascertainment
Pre-fortification
1995
1996
Optional Fortification
1997
1998
Year & quarter of birth
Mandatory Fortification
1999
2000
2001
Fig 1. Three-quarter moving average of the birth prevalence (per 10 000 live births) of
spina bifida according to race/ethnicity for 21 birth defects surveillance programs, 1995–
2002.
Fig 2. Three-quarter moving average of the birth prevalence (per 10 000 live births) of
anencephaly according to race/ethnicity for 21 birth defects surveillance programs, 1995–2002.
Does folic acid prevent birth
defects other than NTDs?
Are NTD Trends Continuing to
Improve?
 We have clear evidence that prevalence
of NTDs improved as a result of folic
acid fortification.
 What’s been happening in the more
recent period?
 Data that follow are from Boulet et al.,
Birth Defects Research Part A (July
2008).
Spina bifida rates by race/ethnicity, 1995-2004
(simple moving average)
6.0
Hispanic
Non-Hispanic white
Non-Hispanic black
Prevalence (per 10,000)
5.0
4.0
3.0
2.0
1.0
1st
2nd
3rd
4th
1st
2nd
3rd
4th
1st
2nd
3rd
4th
1st
2nd
3rd
4th
1st
2nd
3rd
4th
1st
2nd
3rd
4th
0.0
1999
2000
2001
2002
Year and quarter of birth
TM
2003
2004
Anencephaly rates by race/ethnicity, 1999-2004
(simple moving average)
Hispanic
Non-Hispanic white
Non-Hispanic black
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
1st
2nd
3rd
4th
1st
2nd
3rd
4th
1st
2nd
3rd
4th
1st
2nd
3rd
4th
1st
2nd
3rd
4th
1st
2nd
3rd
4th
Prevalence (per 10,000)
4.0
1999
2000
2001
2002
Year and quarter of birth
TM
2003
2004
Prevalence ratio and 95% CI for
post-fortification intervals, 1999-2004
2001-2002/1999-2000
2003-2004/1999-2000
PR
95% CI
PR
95% CI
Spina bifida
0.97
0.90-1.06
0.93
0.86-1.01
Anencephaly
0.88
0.80-0.98
0.78
0.71-0.87
Total
0.94
0.88-1.00
0.87
0.82-0.93
TM
Prevalence ratio and 95% CI for postfortification intervals, non-Hispanic
white infants, 1999-2004
2001-2002/1999-2000
2003-2004/1999-2000
PR
95% CI
PR
95% CI
Spina bifida
0.97
0.86-1.08
0.94
0.83-1.05
Anencephaly
0.82
0.71-0.95
0.74
0.63-0.86
Total
0.91
0.83-1.00
0.86
0.78-0.94
TM
Prevalence ratio and 95% CI for postfortification intervals, non-Hispanic
black infants, 1999-2004
2001-2002/1999-2000
2003-2004/1999-2000
PR
95% CI
PR
95% CI
Spina bifida
1.04
0.82-1.30
0.87
0.69-1.11
Anencephaly
1.22
0.90-1.65
0.82
0.58-1.14
Total
1.10
0.92-1.32
0.85
0.70-1.04
TM
Prevalence ratio and 95% CI for postfortification intervals, Hispanic infants,
1999-2004
2001-2002/1999-2000
2003-2004/1999-2000
PR
95% CI
PR
95% CI
Spina bifida
0.98
0.85-1.14
0.95
0.82-1.09
Anencephaly
0.88
0.74-1.05
0.81
0.68-0.96
Total
0.94
0.84-1.05
0.89
0.80-0.99
TM
Serum folate concentrations (in ng/mL)
for women 15-44 years, NHANES, 19992000, 2001-2002, 2003-2004
35
30
25
20
15
10
5
0
1999-2000
TM
2001-2002
2003-2004
Median serum folate concentrations (ng/mL)
for women 15-44 years by race/ethnicity,
NHANES, 1999-2000, 2001-2002, 2003-2004
Non-Hispanic
white
Non-Hispanic
black
Mexican
American
ng/mL
(95% CI)
ng/mL
(95% CI)
ng/mL
(95% CI)
1999-2000
13.4
(12.2-15.1)
10.0
(9.1-11.2)
11.1
(10.7-11.9)
2001-2002
12.1
(11.3-13.1)
9.5
(9.0-10.4)
10.6
(10.1-11.3)
2003-2004
11.3
(10.6-12.0)
8.5
(7.7-9.2)
10.0
(8.7-10.8)
TM
Preventing the recurrence
of neural tube defects
National Birth Defects Prevention Network
June 2009
Julianne S. Collins, Ph.D.
Greenwood Genetic Center
Greenwood, South Carolina
Neural Tube Defect Recurrence
•
This is the probability of an
additional neural tube defect (NTD)
in a subsequent pregnancy
• The NTD recurrence risk is 2-3% in
the United States
• This is close to 40 times the
background rate of NTDs
Folic Acid Prevents NTDs
•
Folic acid taken prior to conception
and in early pregnancy prevents
most NTDs
• 400 micrograms daily recommended
for women of reproductive age
• 4.0 milligrams daily recommended
for women with a previous NTDaffected pregnancy who are
planning future pregnancies
Folic Acid Prevents NTDs
•
Randomized trails show an 87%
reduction in the NTD recurrence risk
• Observational studies show up to a
100% reduction in risk (Grosse and
Collins, 2007)
Table 2. Results of controlled trials of folic acid supplements for NTD recurrence prevention.
Study
Country
N
Laurence, United 111
1981
Kingdom
MRC,
Europe 1195
1991
Kirke et
Ireland 364
al., 1992
ICMR,
India
279
2000
Pooled
All
1949
NR – Not Reported
NTD rate NTD rate NTD rate NTD rate Percentage Percentage
in those
in those in groups in groups reduction in reduction in
randomized actually randomize not taking risk, intent- risk, actual
to take folic taking
d not to
FA
to-treat
folic acid
acid
folic acid
FA
use
3.3%
0.0%
7.8%
9.0%
58%
100%
(2/60)
(0/44)
(4/51)
(6/67)
1.0%
0.6%
3.5%
3.6%
71%
83%
(6/593)
(3/483) (21/602) (17/477)
0.0%
NR
1.1%
NR
100%
(0/172)
(1/89)
2.9%
NR
7.0%
NR
59%
(4/137)
(10/142)
1.2%
0.6%
4.1%
4.2%
69%
87%
(12/962)
(3/527) (36/884) (23/544)
Table 3. Results of observational studies of folic acid supplements for NTD recurrence
prevention.
Time
period
Study Location
Smithells, Northern
1984
Ireland
ca. 1980
Smithells,
ca. 1980
1984
England
Vergel et
al., 1990
Cuba
NR
Felkner et
al., 2005 Texas 1993-1999
Dean et
South
al., 2007 Carolina 1992-2006
NR – Not Reported
Numbers of
recurrences in
pregnancies
protected by FA
Numbers of
recurrences in
unprotected
pregnancies
Reduction
in
recurrence
risk
0.7% (1/152)
5.0% (12/240)
87%
0.7% (2/302)
4.3% (12/279)
85%
0.0% (0/101)
3.5% (4/114)
100%
0.0% (0/161)
0.0% (0/32)
NA
0.0% (0/364)
4.8% (3/62)
100%
South Carolina NTD Recurrence
Prevention Program
•
Started in 1992 by the Greenwood
Genetic Center (Stevenson et al.
2000) because of the high rate of
NTDs in this state
• Program contacts women with a
NTD-affected fetus, including
women who do not continue their
pregnancy
South Carolina NTD Recurrence
Prevention Program
•
•
•
60% of eligible women enroll
Enrolled women are contacted
frequently by phone and are
provided with counseling and free
folic acid supplements
All enrolled women monitored to
track supplement use and
pregnancy outcomes
South Carolina NTD Recurrence
Prevention Program
•
•
•
85% take folic acid during subsequent
pregnancies
There have been no NTD recurrences
(0.0%) among 364 pregnancies
protected by folic acid (Dean et al. 2007)
There was one recurrence (1.9%) among
53 pregnancies not protected by folic
acid
Is the SC program cost effective?
•
•
•
Cost to administer program in 2003
was ~$155,000
During this time, a total of 35
pregnancies occurred among
women enrolled in the program
Average cost of program was
~$4,400/protected pregnancy
(Grosse et al, December 2008
AJPM.)
Is the SC program cost effective?
•
•
•
This cost is comparable to other
types of prevention programs.
Different types of recurrence
prevention programs are now being
studied to determine if they are
more cost effective.
(Grosse et al, December 2008
AJPM.)
So, How Are We Doing With Recurrence
Prevention Efforts?
 Both the March of Dimes and the CDC
(among other agencies) have funded efforts
to deliver recurrence prevention services to
women whose pregnancies were affected
by neural tube defects.
 A national survey of these activities was
conducted during 2005 (Collins et al.,
November 2009, Birth Defects Research
Part A).
Methods that past and present recurrence prevention
projects (n=17) used to contact mothers
Project Contact Methods
N
% of All Projects
Mail
12
71%
Telephone
8
47%
Through physician
4
24%
In person
3
18%
At a clinic
3
18%
Reasons why 17 states do not have recurrence
prevention projects
10
# of Responses
8
6
4
2
0
Staffing
limitations
Lack of funds Lack of priority*
Privacy
concerns
Other state programs
•
Only 15 state programs have or are
planning recurrence prevention
projects
• Implementing additional recurrence
prevention projects should be an
urgent national public health priority
(Collins et al., November 2009, Birth Defects
Research Part A)
Fortification increases
survival and decreases the
severity of spina bifida
National Birth Defects Prevention Network
June 2009
Russell Kirby, Ph.D.
Background
•
The prevalence of neural tube
defects (NTDs) has decreased
since folic acid fortification began
• However, NTDs continue to occur,
as do deaths in infants with NTDS
Objective
•
The specific objective of this study
was to assess whether survival of
infants with NTDs has improved
during the period of folic acid
fortification in the United States
•
Bol, Collins, Kirby, Pediatrics 2006
Methods
•
•
A retrospective cohort analysis
using NTD data provided by 16
states as part of a collaboration
through the National Birth Defects
Prevention Network
Includes infants born between 1995
and 2001 diagnosed with a neural
tube defect
Analyses
•
Proportional hazards regression
was performed using period of birth
(pre-folic acid fortification, optional
fortification, mandatory fortification)
and selected maternal, pregnancy,
and birth characteristics
Results
•
There were 2,841 births with spina bifida.
Infant survival across the three periods of
birth was:
•
•
•
•
Pre-fortification: 90.3%
Optional fortification: 90.5%
Mandatory fortification: 92.1%
Infants with spina bifida born during the
mandatory fortification period had a
reduced risk of death during infancy
Conclusion
•
•
Survival of infants with spina bifida
and encephalocele has improved
during mandatory folic acid
fortification of the food supply
Subsets of the population of infants
with neural tube defects experience
increased risk of death during
infancy
•
•
From 1975-1999, both the
prevalence and severity of NTDs
significantly decreased at Coombe
Women's Hospital (P < 0.0001).
Cotter and Daly, 2005. Eur J Obstet
Gynecol Reprod Biol 119(2): 161163.
Future steps
•
Continued multi-program
collaborations are necessary for
continued study of NTD prevalence
and outcomes as well as NTD
prevention efforts
Brief Summary for Those Who Are Knitting,
Doing Crossword Puzzles, or Discerning the
Geometric Pattern in the Carpeting
 Rigid adherence to the evidence-based
practice paradigm will result in important
findings with clinical implications being
overlooked.
 Folic acid fortification, in concert with preand interconceptional care, has
significantly reduced the prevalence of
neural tube defects in the US.
Brief Summary for Those Who Are Knitting,
Doing Crossword Puzzles, or Discerning the
Geometric Pattern in the Carpeting
 However, our failure to adequately fund
continued efforts in folic acid education,
advocacy, and recurrence prevention together
with fortifying flour at perhaps too low a level
and failing to fortified unenriched grain and
corn-based products has reduced the
effectiveness of these interventions.
 The lessons learned from this experience
should inform the process of translating
scientific findings into health policy and public
health initiatives in the future.
Contact Information
 Russell Kirby, PhD, MS, FACE
 Telephone: 813-396-2347
 Email: [email protected]
 Julianne Collins, PhD
 Telephone: 864-388-1737
 Email: [email protected]