Joel Zlotogora,
Department of Community Genetics
Health Ministry. ISRAEL,
Yona Amitai, Dorit Nitzan Kaluski, Alex Leventhal, Avi Israeli
Send response to journal:
Re: Data from the National NTD registry in Israel
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We read with interest the article by Botto et al 1 on the effect of folic acid recommendations in an international retrospective cohort, although we do have some reservations concerning the data from Israel.
The local "Israeli registry" used by the authors includes only three out of 25 Israeli general hospitals, and are located in the central part of country. This restricted registry reports on 1.3 cases of open neural tube defects per 10,000 births between the years 1988-1998, a strikingly low rate, in particular when compared to the other participating countries. Another surprising observation is the very low rates of termination of affected pregnancies. However, the real situation in Israel as a whole is completely different as demonstrated in several surveys (cited in 2). A national Israel NTD registry established in 1999 collecting data forms all the diagnosed cases, and from multiple sources 2. The rate of open neural tube defects for 1999 and 2000, as revealed by the National NTD Registry, was 15.1 per 10,000 live births with a 62 % rate of pregnancy termination (table 1). Whereas the rates reported in the article from the local "Israeli registry" are even lower than those obtained at birth in the general population, demonstrating a strong population bias of the clients served by these three hospitals.
The second point deals with the recommendation of folic acid supplementation. In Israel as pointed by Botto et al 1, the Health Ministry issued the recommendation for supplementation with folic acid toward the second half of the year 2000. Studies done in Israel had shown that prior to this recommendation only 5.2% of the women actually consumed the folic acid supplement before and at the beginning of their pregnancy and that. Whereas two years after the publication of this recommendation there was a marked increase to 30.5% 3. In the same period we have observed a decrease in the rate of open neural tube defects both among Israeli Jews and Arabs. Looking back at the two years before the recommendation (1999, 2000) and comparing them with the two years in which full pregnancies were after the recommendation (2002-2003) a 20% decrease in the rate of neural tube defects has been observed (Table 1).
There is another decision to encourage food fortification with folic acid in Israel, which has been only partially implemented, and practically there has been no remarkable change during these years. Therefore it is probable that the decrease in the rate of neural tube defects may be attributed to the increased usage of supplementation.
While these are preliminary observations they indicate an effect of folic acid that is the one expected according to the rate of use of supplementation. A similar trend seems to exist also for 2004 but we are still processing the complete data.
References
1.Botto LD, Lisi A, Robert-Gnansia E, Erickson JD, Vollset SE, Mastroiacovo P, Botting B, Cocchi G, de Vigan C, de Walle H, Feijoo M, Irgens LM, McDonnell B, Merlob P, Ritvanen A, Scarano G, Siffel C, Metneki J, Stoll C, Smithells R, Goujard J. International retrospective cohort study of neural tube defects in relation to folic acid recommendations: are the recommendations working? BMJ. 2005 Feb 18; [Epub ahead of print]
2.Zlotogora J, Amitai Y, Kaluski DN, Leventhal A. Surveillance of neural tube defects in Israel. Isr Med Assoc J. 2002 4:1111-1114.
3.Amitai Y, Fisher N, Haringman M, Meiraz H, Baram N, Leventhal A. Increased awareness, knowledge and utilization of preconceptional folic acid in Israel following a national campaign. Prev Med. 2004 39:731-737.
Table 1. Non syndromic open neural tube defects in Israel 1999-2003 (Numbers and rate per 10,000 live births)
| Year
| 1999 |
2000 |
2001 |
2002 |
2003 |
| N live births
| 131936 |
136390 |
136638 |
139535 |
144936 |
| N NTD live newborns (rate)
| 57 (4.3) |
62 (4.5) |
69 (5.0) |
44 (3.2) |
39 (2.7) |
| N Total NTD (rate)
| 196 (14.9) |
200 (14.8) |
198 (14.5) |
156 (11.1) |
167 (11.5) |
Competing interests:
None declared
|
Poor use of folic acid tablet supplements periconceptionally explains much |
11 March 2005 |
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Joel Ray,
Clinician-Scientist
St. Michael's Hospital, University of Toronto, M5A 2X3
Send response to journal:
Re: Poor use of folic acid tablet supplements periconceptionally explains much
|
I read with interest Botto et al's review of the unchanged prevalence
of NTD across the last decade, despite awareness of the benefits of tablet
supplement use (BMJ 2005; 330: 571).
We recently completed a systematic overview of all published survey
studies of folic acid tablet use periconceptionally <1>. It is
unfortunate that Botto and colleagues did not mention our review in their
article, only because it provides the major explanation why there has
observed little or no decline in the rate of NTDs in countries that lack
folic acid food fortification.
In our review of 49 studies, the reported rate of folic acid tablet
supplement use periconceptionally ranged from 0.5% to 52% <1>.
Significant predictors of reduced periconceptional folic acid use were a
low level of formal education, immigrant status, young maternal age, lack
of a partner and an unplanned pregnancy. Four studies examined the effect
of mass media campaigns on periconceptional folic acid use; the reported
rates increased significantly, by a factor of 1.7 to 7.2, but in no study
was the post-campaign rate above 50%.
Enrichment of food with adequate amounts of folic acid may be the
only viable approach to making significant inroads into the prevention of
neural tube defects. Data from Canada <2, 3> and the US <4>
support this concept.
Reference
<1> Ray JG, Singh G, Burrows RF. Evidence for suboptimal use of
periconceptional folic acid supplements globally.
BJOG 2004; 111: 399-408.
<2> Ray JG, Meier C, Vermeulen MJ, Boss S, Wyatt PR, Cole DEC.
Association of neural tube defects and folic acid food fortification.
Lancet 2002; 360: 2047–8.
<3> Persad VL, Van den Hof MC, Dube JM, Zimmer P. Incidence of
open neural
<4> Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD, Wong LY.
Impact of folic acid fortification of the US food supply on the occurrence
of neural tube defects. JAMA 2001; 285: 2981-6.
Competing interests:
None declared |
|
Another myth? |
14 March 2005 |
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Mark Selinger,
Consultant in Feto-Maternal Medicine
Royal Berkshire Hospital, Reading, Berks
Send response to journal:
Re: Another myth?
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Before advocating global folic acid food supplementation, perhaps
your authors should revisit the published studies on NTD prevention. The
Cochrane Database analyses four studies. Only one, Czeizel 1994, was
carried out on low risk women and showed a statistically insignificant
effect. Two more studies suggest no benefit. The fourth, the MRC trial
recruited only women who had suffered a previously affected fetus/baby.
Why treat all men and almost all women with Folic acid for their
whole lives when the evidence is so poor?
Competing interests:
None declared |
|
Re: Another myth? |
18 March 2005 |
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Lorenzo Botto,
Assistant Professor of Pediatrics
Deparment of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah USA 84132
Send response to journal:
Re: Re: Another myth?
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The evidence that folic acid reduces the occurrence of neural tube
defects is robust, consistent and has been reviewed repeatedly. In one
such review (New England Journal of Medicine 1999;341:1509-19), the
preventive effect was shown to have been established in settings that
varied, among other factors, by background prevalence of neural tube
defects, ethnic composition of the population, geography, time of study,
and study design. It supported by genetic evidence of polymorphic folate
genes.
The preventive effect has been shown in observational studies,
clinical trials, a community intervention study, and now, as noted also in
our article and another rapid response, also in post-fortification
assessments.
The Cochrane review (www.cochrane.org/cochrane/revabstr/AB001056.htm)
cited by Dr Selinger as saying differently in fact states in its
conclusions that “periconceptional folate supplementation has a strong
protective effect against neural tube defects. Information about folate
should be made more widely available throughout the health and education
systems”.
Competing interests:
None declared |
|
Re: Data from the National NTD registry in Israel |
19 March 2005 |
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Lorenzo Botto,
Assistant Professor of Pediatrics
Deparment of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah USA 84132
Send response to journal:
Re: Re: Data from the National NTD registry in Israel
|
We thank Dr Zlotogora and collaborators for their contribution and
update on neural tube defects in Israel since 1999, beyond the study
period in our article. The rates from their registry are higher that those
from the Israel program that is part of the International Clearinghouse,
for reasons that Zlotogora and collaborators suggest and possibly also
because of differences in the underlying populations, such as the relative
proportion of Arab and Jewish births that are covered in the two systems.
We are reviewing these data. We also look forward to the work of Dr
Zlotogora and collaborators in understanding the role of supplement use in
modifying background rates of neural tube defects in Israel. I hope we can
exchange further information in the future for more complete tracking of
the situation.
Finally, we thank Dr Zlotogora and collaborators for their support of
and work towards supplementation and fortification, and we look forward
with them to when all women in Israel can reap the benefits of folic acid.
Competing interests:
None declared |
|
Re: Need for folic acid public awareness campaign |
19 March 2005 |
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Lorenzo Botto,
Assistant Professor of Pediatrics
Deparment of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah USA 84132
Send response to journal:
Re: Re: Need for folic acid public awareness campaign
|
I thank Dr Hicks for his succint argument for educating women and
health professionals about the benefits of folic acid. I agree completely
and raise the further point, which was perhaps implied by Dr Hicks, that
education campaigns should be sustained over time, as every year a new
cohort of women enters pregnancy (and perhaps a new cohort of medical
professionals enters practice) who may not have been exposed to preceding
campaigns.
Competing interests:
None declared |
|
Re: Poor use of folic acid tablet supplements periconceptionally explains much |
19 March 2005 |
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Lorenzo Botto,
Assistant Professor of Pediatrics
Deparment of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah USA 84132
Send response to journal:
Re: Re: Poor use of folic acid tablet supplements periconceptionally explains much
|
We thank Dr Ray for highlighting his review article on folic acid
use. We were aware of his scholarly work as the article was completed, but
timing and space limitations led us to cite selected primary sources.
Dr Ray's article and ours both make the point that folic acid is used
in most surveyed areas by a minority (often a small minority) of women of
childbearing age or entering pregnancy, and that supplement use often
mirrors social or economic disparities.
For these reasons, as women are educated about supplementation,
fortification should also be promoted as a way to sustain primary
prevention on a population level for all women of childbearing age. As Dr
Ray notes, fortification works in the countries that have implemented it.
Competing interests:
None declared |
|
Re: Data from the National NTD registry in Israel |
18 April 2005 |
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Patricia A Boyd,
Clinical Geneticist, Senior Research Fellow
National Perinatal Epidemiology Unit OX3 7LF
Send response to journal:
Re: Re: Data from the National NTD registry in Israel
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Re NTD Data from England and Wales
Zlotogrgora (rapid response 5 March 2005) has some reservations
concerning the Israeli data on neural tube defects (NTDs) used in the
study reported by Botto et al on the effect of folic acid recommendations
in an international retrospective cohort (1). Similarly there needs to be
some caution in interpreting the NTD data from England and Wales.
Ascertainment of congenital anomalies by the national register for
England and Wales (National Congenital Anomaly System) has been shown to
be low and non-uniform in comparison with ascertainment by local registers
covering the same population (2). This is illustrated by the higher
prevalence of NTDs in the UK in the EUROCAT (www.eurocat.ulster.ac.uk)
paper addressing prevention of NTDs, which appeared in the same issue of
the BMJ (3). The latter paper uses data from EUROCAT population based
congenital anomaly registers, covers the same time period and an
overlapping, but not identical, population. It reports an incidence of
NTDs much higher than that quoted by Botto et al for England and Wales and
Ireland.
PA Boyd
References
1. Botto LD, Lisi A, Robert-Gnansia E, Erickson JD, Vollset SE,
Mastroiacovo P, Botting B, Cocchi G, de Vigan C, de Walle H, Feijoo M,
Irgens LM, McDonnell B, Merlob P, Ritvanen A, Scarano G, Siffel C, Metneki
J, Stoll C, Smithells R, Goujard J. International retrospective cohort
study of neural tube defects in relation to folic acid recommendations:
are the recommendations working? BMJ 2005; 330: 571-3
2. Boyd PA, Armstrong B, Dolk H, Botting B, Pattenden S, Abramsky L,
Rankin J, Vrijheid M, Wellesley D. Congenital anomaly surveillance in
England - ascertainment deficiencies in the national system. BMJ 2005;
330:27-9
3. Busby A, Abramsky L, Dolk H, Armstrong B. Preventing neural tube
defects in Europe: population based study. BMJ 2005; 574-5
Competing interests:
None declared |
|
A proactive approach to increase the periconceptional use of folic acid works. |
2 May 2005 |
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Willemijn Meijer,
PharmD
Groningen University Institute for Drug Exploration, the Netherlands,
Denhard de Smit, and Lolkje de Jong-van den Berg
Send response to journal:
Re: A proactive approach to increase the periconceptional use of folic acid works.
|
Two recent studies showed that a policy stating health providers
should recommend women planning to become pregnant to use folic acid (FA)
periconceptionally without any further action is not effective to
influence trends in neural tube defects (NTDs) (1,2).
In the Netherlands, after a national mass media campaign intended to
inform patients as well as professionals about FA, a slight decrease in
the prevalence of NTDs was detected (1.86 to 1.60/1000) (3). However, this
approach does not target women individually and a sustained effect cannot
be expected from a one-off campaign. Indeed, in 2002 the periconceptional
use of FA did not exceed the 36% and is even lower among lower educated
women (4). Food fortification in addition to implementation of
recommendations on supplementation are urgently required. In this respect
proactive approaches can be succesful, however, the problem remains that
health providers only target a few women before they attempt to become
pregnant. Since approximately 70% of Dutch women take oral contraceptives
(OC) before their first pregnancy and thus visit their pharmacy regularly,
we developed an proactive intervention in pharmacies which aimed to inform
and motivate OC-using women to take FA before pregnancy.
A randomised pilot study showed that women from the intervention
pharmacies had greater knowledge concerning the protective effects of FA
compared with women from reference pharmacies. More importantly, the
current FA-use among women who intend to become pregnant was higher in the
intervention than the reference group (62.5 vs 30.8% among nulligravidae
and 40.0 vs 26.7 in women with a previous pregnancy) (5). These data
strongly suggest that information provided contineously by pharmacies,
educate and motivate women planning pregnancy.
1. Botto LD, Lisi A, Robert-Gnansia E, Erickson JD, Vollset SE,
Mastroiacovo P et al. International retrospective cohort study of neural
tube defects in relation to folic acid recommendations: are the
recommendations working. BMJ 2005;330:571-573.
2. Busby A, Abramsky L, Dolk H, Armstrong B, a Eurocat Folic Acid
Working Group. Preventing neural tube defects in Europe: population based
study. BMJ 2005;330:574-75.
3. KM van der Pal-de Bruin, H Kateman, E Zwane, PGM van der Heijden,
SE Buitendijk. Influence of folic acid use on trends in neural tube
defects (in dutch). TNO-report PG/JGD2003-320.
4. Walle HEK de, Jong-van den Berg LTW de. Insufficient folic acid
intake in the Netherlands: What about the future? Teratology 2002;66:40-3.
5. Willemijn M. Meijer, Denhard J. de Smit, Renate A. Jurgens and
Lolkje T. W. de Jong-van den Berg. Improved periconceptional use of folic
acid after patient education in pharmacies: promising results of a pilot
study in the Netherlands. IJPP 2005;13: 47-51.
Competing interests:
None declared |
|
Re: A proactive approach to increase the periconceptional use of folic acid works. |
4 May 2005 |
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Godfrey P. Oakley, Jr.,
Research Professor of Epidemiology, Rollins School of Public Health of Emory University
30322
Send response to journal:
Re: Re: A proactive approach to increase the periconceptional use of folic acid works.
|
The prevalence of spina bifida and anencephaly among women who
consume 400 micrograms of synthetic folic acid a day before and during the
early months of pregnancy is about 0.5 per 1000. [1] The rate of around
1.5 per 1000 in the Netherlands represents a 300 percent epidemic of folic
acid-preventable spina bifida and anencephaly. The way to end this
epidemic is for the Dutch government to require folic acid fortification
of flour, an act they have considered on two occasions and refused to do.
Mandatory folic acid fortification of flour in the United States and
Canada has been implemented for about 7 years and has been shown to be
safe and highly effective in preventing birth defects and lowering
homocysteine concentrations for the population. [2] While I have no
objection to education by pharmacists and I think that folic acid should
be available within contraceptive pills, note my disclosure statement,
what is urgently needed is for all governments of the world to require
immediate folic acid fortification of centrally processed and widely eaten
food. [3] Governmental officials in Nigeria have been viewed as
irresponsible for their role in the cases of polio that continue to occur.
If we had an epidemic of polio in Europe and the governments did not
immediately respond to it, they would be viewed as irresponsible. The
lack of action by European governments is responsible for the current
epidemic of infantile paralysis caused by spina bifdia. Is the failure of
European governments to required folic acid fortification and end the
epidemic of birth defects any less irresponsible than the actions taken by
the government officials in Africa that has resulted in unnecessary cases
of polio?
References
1. Berry, R.J., et al., Prevention of neural-tube defects with folic
acid in China. China-U.S. Collaborative Project for Neural Tube Defect
Prevention [corrected; erratum to be published]. New England Journal of
Medicine, 1999. 341(20): p. 1485-90.
2. Oakley, G.P., Jr., et al., Scientific evidence supporting folic acid
fortification of flour in Australia and New Zealand. Birth Defects
Research, 2004. 70(11): p. 838-41.
3. Oakley, G.P., Jr., K.N. Bell, and M.B. Weber, Recommendations for
accelerating global action Ato prevent folic acid-preventable birth
defects and other folate-deficiency diseases: meeting of experts on
preventing folic acid-preventable neural tube defects. Birth Defects
Research, 2004. 70(11): p. 835-7.
Competing interests:
I am a co-inventor (while at CDC, compensation, if any, will be under the regulations of CDC) of a patent that covers adding folic acid to contraceptive pills and I am a paid consultant to Ortho McNeil on this issue. |
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Re: Re: Data from the National NTD registry in Israel |
5 May 2005 |
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Lorenzo D Botto,
Assistant Professor, Senior Epidemiologist
University of Utah, Dpt Pediatrics
Send response to journal:
Re: Re: Re: Data from the National NTD registry in Israel
|
We appreciate dr Boyd's information. High sensitivity of a monitoring
program is good. However, it is not necessarily relevant to the study.
In monitoring trends one is primarily concerned in changes in rates,
not in absolute value. Because rate changes are the focus, what matters
most is that the sensitivity of a monitoring program remains constant.
Thus, it was possible to show the effectiveness of fortification in
reducing neural tube defect rates in the United Statets by using birth
certificates, which are known to be rather insensitive reporting sources
of birth defects (but constantly so).
Competing interests:
None declared |
|
The Maternal - Fetal Nutritional Link |
17 May 2005 |
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Henry C. Clarke,
medical doctor
1027 Ottawa Street, Windsor, Ontario, Canada, N8X 2E3
Send response to journal:
Re: The Maternal - Fetal Nutritional Link
|
There are fixed lower classes, “disadvantaged groups” within nations.
It has been assumed that hereditary factors pass from mother to fetus,
from one generation to the next creating a class system, with inferior
hereditary factors resulting in an untreatable fixed lower class. Evidence
of a maternal/fetal cellular nutritional link was demonstrated by my work
with B2 in 1971(1). B-vitamins are important for development of the brain
and central nervous system. Deficiency in the mother can adversely affect
the development of the fetal brain and CNS. Of ominous significance is
that in the human fetus multiplication of the brain cells ceases shortly
after birth. This link, from one generation to the next, is the key for
interpreting the fixed lower classes within and between nations.(2)
The treatment for the fixed lower class condition was derived from my
later work which offered the principle of “preconception nutritional
treatment” in Letter to the Editor: Am J Obstet Gynecol 1984;2004:197. In
1992 the U.S. Public Health Service and the American Public Health
Association were urging folic acid supplements before conception. In 1996
The FDA mandated that by January 1998, all bread and grain sold in the
United States be fortified with folic acid, thus securing treatment for
all mothers in the preconception. The gross NTD’s were decreased. Canada
followed. This originated from my work which had envisaged treatment of
all factors of deficiency in the mothers, particularly the B-complex, but
not restricted to folic acid.
Treatment with folic acid, without supplementation of the other B-
complex vitamins, can aggravate deficiency in mal nourished populations.
Increase in Red Blood Cell mass can cause decrease in Mean Corpuscular
Riboflavin Concentration which affects the fetus.(2)In two years, after
treatment with folic acid in a general population, serum B12 (pmol/L) fell
from 276 to 270, -6(p<0.001).(3) This can be particularly harmful to
vitamin B deprived populations, confirming a lower class status from
generation to generation.(4) The concurrent B-complex deficiencies have
not been assessed or treated.
References
1. Clarke HC. Relationship between whole blood riboflavin levels in mother
and prenate. Am J Obstet Gynecol 1971;9:43-6
2. Daniel WW. Applied non-parametric statistics: rank correlation and
other methods of association. 2nd ed. Boston (Ma): PWS-KENT Publishers;
1991. p. 377-80
3. Ray JG. Folic acid food fortification in Canada. Table 1. Red Cell
Folate and Serum B12 Concentrations before and after folic acid
fortification. Nutrition Reviews, Vol. 62, No.6. 2004: (11) S35-S39.
4. Clarke HC. Impact of folic acid fortification in the United States.
Letter to the Editor. Obstet. Gynecol. 2004;104:197.
Competing interests:
None declared |
|
The cellular nutritional link between Mother and Fetus |
26 May 2005 |
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Henry C. Clarke,
M.D.
1027 Ottawa street, Windsor, Ont., N8X 2E3 Canada
Send response to journal:
Re: The cellular nutritional link between Mother and Fetus
|
This link published by Clarke in 1971, is the key for interpreting
the social classes within and between nations. (Clarke HC. Relationship
between whole bloods riboflavin levels in mother and prenate. Am J Obstet
Gynecol 1971;9:43-6.)This was validated by the work of others.(Daniel ww.
Applied non-parametric statistics: rank correlation and other methods of
association. 2nd ed. Boston (MA): PWS-KENT Publishers; 1991. p.377-80). In
1984 in letter to the Editor Clarke offered the principle of "Pre-
conception nutritional treatment" (Am J Obstet Gynecol 1984;2004:197). The
U.S. Public Health Service, and the American Public Health Association,
with Health Canada adopted this principle for folic acid fortification. No
credit has been given to the work of Clarke. Application without treatment
of other B-vitamins can confirm the lower class status of within and
between nations. Nutriton not hereditary factors maintain the fixed class
systems.
Competing interests:
None declared |
|
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Need for folic acid public awareness campaign