pp. 390-393 in Bioethics in Asia

Editors: Norio Fujiki and Darryl R. J. Macer, Ph.D.
Eubios Ethics Institute

Copyright 2000, Eubios Ethics Institute All commercial rights reserved. This publication may be reproduced for limited educational or academic use, however please enquire with the author.

F11. Primary prevention is better than secondary prevention

Andrew E. Czeizel and Istv_n Dud_s.

National Institute for Health Promotion and WHO Collaborative Centre for Community Control of Hereditary Diseases, Budapest, Hungary

At present, about 25% of infant mortality is caused by congenital abnormalities (CAs) in industrialized countries. However, CAs are among the leading causes of death, with a high number of life years lost and impaired life. Another important feature of CAs is that they represent a defect condition, because it is difficult to achieve a complete recovery. Thus, prevention is considered the only optimal solution.

Among different CAs, the CAs of central nervous system are one of the most frequent and serious developmental disturbances.Anencephaly and spina bifida (aperta or cystica) are the major classes of neural tube defects (NTDs). Although the genetic (polygenic) background of nonsyndromic, i.e., the so-called isolated NTDs (92% of all cases) is obvious because recurrence in first degree relatives is 10 times higher than their occurrence , this group of CAs is very sensitive to environmental factors. The latter is indicated by the very wide range (0.5-12/1000) of NTD incidences in different populations, rapid secular changes in their occurrence, seasonal variation of births with NTD, and mainly by their very obvious socioeconomic status dependence: The risk of NTDs was found to increase from a low risk in the highest class to an above-average risk in the lowest class in the United Kingdom and some other countries.

The history of medical care in cases with NTD

The history of NTDs shows that we can modify our destiny by the help of science. It is worth differentiating five stages of their history (1). Before the 1960s nearly all NTDs were fatal. Anencephaly is obviously a lethal CA. However, the great majority (95%) of cases with spina bifida cystica also died before 1960 (2). In the 1960s pediatric surgeons introduced very early complex medical intervention and the lives were saved in the majority of spina bifida cases. However, this success needed a tremendous “cost”. The greater number of survivals had multiple handicaps including mental retardation due to hydrocephalus, palsy of lower limbs with secondary clubfoot and incontinence of urine due to the damage of spinal cord (3). Thus the selective criteria of surgical intervention was introduced to reduce the production of multiple handicapped children in the 1970s. This stage of NTD’s history resulted in a great psychological and moral burden for physicians because they had to decide the question: to be or not to be. Really this procedure was the manifestation of passive euthanasia (4).

Thus the next stage of development was a progress. In the 1980s prenatal screening was introduced, resulting in a significant drop in the NTD fetuses; however , it increased the number of pregnancy terminations. The prenatal screening for the detection of NTD fetuses is based on the measurement of the maternal serum a -fetoprotein (MS-AFP) and/or ultrasonography. The MS-AFP is measured between 16 and 18 week of gestation after the determination of gestational age by ultrasound examination. The latter is appropriate to immediately diagnose anencephalic fetuses. Values of MS-AFP > 2.0 - 2.5 MoM (multiples of median) for the gestational age are considered suspect. The proportion of abnormal high MS-AFP that can be confirmed by ultrasonographic examinations varied between 1.2 and 3.9% of pregnant women. If it is negative, generally it is recommended to repeat MS-AFP. If the second result is also abnormal and a high- resolution ultrasonographic examination cannot detect NTD or other causes of a high MS-AFP (multiple fetuses, fetal death, other CAs, maternal diabetes mellitus), amniocentesis is offered to women because amniotic fluid acethylcholinesterase is confirmatory for the diagnosis of NTD. After the diagnosis of fetal NTD, parents are informed about this serious CA. Thus, parents have to choose between two evils. On the one hand to terminate the pregnancy which was in general planned and wanted. On the other hand to continue the pregnancy but to calculate with the long term medical, psychological and financial consequences of spina bifida in their baby. The majority of parents select the termination of pregnancy as less of an evil which is obviously one form of active euthanasia. We have to accept the decision of parents, however, we have to be aware of the fact that it is a last resort rather than an optimal solution.

We cannot measure the success of new genetics by the number of terminated pregnancies (or the devastated fetuses). As we believe it is not possible to measure the success of surgery by the number of amputation in lower limbs due to vascular stenosis. Surgeons do it to save the lives but it also is not an optimal solution. Thus we have to do our best to introduce the primary prevention of NTD, as an optimal approach (5). We are happy to inform you that in the 1990s, we have the chance to prevent the maldevelopment of neural-tube (and other organs) by the periconceptional folic acid containing multivitamin supplementation.

Primary prevention of NTDs

The documented start of the primary prevention of NTDs dates back to 1976. Prof. Smithells hypothesized that among triggering environmental factors in the origin of NTDs, undernutrition could be the common denominator, and his group tested this hypothesis: A lower concentration of red cell folate and other vitamins was found during the first trimester of pregnancy in women who later gave birth to an infant with NTD than in matched controls (1). These findings prompted Smithells and his group to organize the first intervention study (2). In general, occur postconceptional d.15 and 28 in humans, i.e., at the critical period of NTDs most women are unaware of their pregnancy. Thus , "periconceptional" supplementation of folic acid -containing multivitamin should commence at least 28 days prior to conception and to continue to the date of the second missed menstrual period. The final results of the Smithells et al.study were published separately for the Yorkshire region of the United Kingdom (3) and Northern Ireland (4). However, the 91 and 83% reduction in NTD recurrence, respectively, were not accepted by some experts because of possible selection bias. Two ethical committees refused to give permission for the original protocol of the study, i.e., for a randomized clinical trial; thus the control group was made up of women who had had one or more previous infants with NTDs and were already pregnant when referred to the study centers or declined to take part in the trial.

In the early 1980s, the Medical Research Council (MRC) (5)in the United Kingdom decided to organize a multicenter (43% of participants came from Hungary) double-blind randomized study. This trial indicated that a pharmacological dose (4 mg) of folic acid supplementation alone can reduce NTD recurrence significantly (by 71%).

However, there were two major questions following the publications of the "recurrence" studies and the Hungarian randomized, double-blind controlled trial attempted to provide data to answer these questions. The first question was:"Does folic acid containing-multivitamin supplemetation also reduce the risk of first occurence of NTD? "About 95% of women who deliver infants with NTD have no previous NTD pregnancies. Thus, one of the critical goals of the Hungarian trial was to determine the efficacy of this new primary preventive method in the reducion of the first occurence of NTD.The second question was connected with the dose. The pharmacological dose (e.g. 4 mg) of folic acid may have some adverse effects;thus, it cannot be recommended for the population at large and /or without medical supervision. The Hungarian intervention trial, therefore, tested the preventive effect of a physiological dose (0.8mg) of folic acid as one component of a periconceptional multi-vitamin supplement. The Hungarian trial was launched on February 1, 1984 and the intervention was completed on April 30,1992. Pregnancy outcomes were evaluated until the end of April 1993 and the postnatal follow-up continued until the end of April 1994. As it can be seen in Table 1, no NTD case was found in the multivitamin group, whereas 6 NTD cases occured in the placebo-like trace-element group (p=0.01). Thus, the Hungarian trial demonstrated that a multivitamin containing 0.8 mg of folic acid prevented the first occurences of NTD.

  1. At present there are three possibilities to provide appropriate multivitamin/folic acid consumption for women of childbearing age who are capable of becoming pregnant. Consumption of folate-rich and other vitamin-rich diet. McPartlin et al. (6) study suggested that the optimal daily intake of folate in the pre-and postconceptional period is about 0.66 mg. However, the usual daily intake of folate in Europe is about 0.16-0.20 mg. It is difficult to imagine a 3.3-3.7-fold increase in folate intake every day in anticipation of conception. In addition, food folate polyglutamates are converted to monoglutamates by an enzyme: conjugase in the upper part of the small intestine and as the study of Cushelly et al. (7) shows, consumption of extra folate from natural food is relatively ineffective at increasing folate status.
  2. Periconceptional supplementation would be a simple and useful approach; however, about 50% of pregnancies are unplanned in the United States, Hungary, and many other industrialized countries. (Only the Netherlands have a 90% proportion of planned and/or wanted pregnancies.) In addition an appropriate pre -or periconceptional care is needed for the practical delivery of periconceptional multivitamin/folic acid supplementation, as in Hungary in the Hungarian Optimal Family Planning Service.
3. Food fortification seems to be the most practical means of supplamentation and, it is in discussion in some countries, e.g. United States, United Kingdom, Hungary. This public health action is comparable to the prevention of goiter by the addition of iodine to salt.

All the three possibilities should be pursued in parallel to provide options for women who are capable of becoming pregnant.

Table 1: The Data of Intervention Studies for the Reduction of NTD Recurrences and Occurrences

Type Method Country Supplement With supplement Without supplement % Risk
       

No

%

No

%

reductn.

Recurrence Non-

randomized
Yorkshire (20) Northern Ireland (21) Multivitamina

1/187

4/511

0.5

0.8

18/320

17/353

5.6

4.8

91

83

  Randomized Multicenter MRC (23) Folic Acid (4mg)

Folic Acid + other vitamins

Total

Other vitamins

2/298

4/295

6/593

8/302

0.7

1.4

1.0

2.6

13/300

21/602

4.3

3.5

84

71

Occurrence Randomized Hungary (25) Multivitaminb

0/2471

0.0

6/2391

0.25

100

aIncluded 0.36 mg folic acid

bIncluded 0.8 mg folic acid

cIncluding cases supplemented with 'other' vitamins

Primary versus secondary prevention

The efficacy of the so called secondary prevention is growing and considerable. This is explained by the increasing effectiveness of prenatal examinations as a result of the improvement of diagnostic methods (e.g. ultrasonography) and new approaches (e.g., DNA probes). However, we have to do our best to develop and to introduce primary preventive methods instead of the secondary one, i.e.,selective abortion. The history of NTD offers a good example to demonstrate the feasibility of this concept.

At present , both primary and secondary preventive methods are available for NTD. In general (i.e. low-risk) populations the detection rate (i.e., sensitivity) of MS-AFP testing for open NTD varies from 72-91% and the specificity from 96.2-98.7% (8).

Periconceptional folic acid-containing multivitamin supplementation as a primary preventive method offers an appropriate alternative with the same efficacy (83-100%) (see Table 1). The evaluation of adverse effects shows obviously a better picture for multivitamin supplementation. Very rare adverse effects may occur only after the use of a pharmacological dose of folic acid in patients with pernicious anaemia or with particular epilepsy. Thus only multivitamins including physiological dose (< 1 mg) of folic acid is recommended. The cost is much lower in the primary prevention compared to secondary one. In Hungary the ratio of cost in periconceptional multivitamin supplementation and fetal diagnosis + termination of pregnancy is 1:10-25 . Finally the main advantage is the lack of pregnancy termination in primary prevention.

In addition the final database of the Hungarian trial indicated a significant reduction in two CA groups (9,10). Nine cases with CAs of the urinary tract were found in the trace-element group and only two in the multivitamin group (c 2 =4.70; p= 0.03; relative risk:0.22CI 95%:0.05,0.99). The difference was most obvious in the obstructive CAs of the urinary tract. In addition, there were two offspring with renal agenesis in the trace element group. The combined rate of the obstructive CA groups of the urinary tract and renal agenesis (1 vs 8) also showed a significant difference between the two study groups (c 2 = 5.69; p = 0.017 ).

There were 10 infants with cardiovascular CAs in the multivitamin group and 20 in the trace - element group. The presence of cardiovascular CAs was confirmed before 1 year of age by cardiological consultation (including echocardiography or cardiac catheterization ), surgery or autopsy. One case with aortic stenosis was familial in the multivitamin group; after the exclusion of this case the difference was significant (c 12 = 4.57; p = 0.032). The difference of cardiovascular CAs is mainly explained by two cases of ventricular septal defect in the multivitamin group and eight cases in the trace - element group (c 2 =3.81; p = 0.051). The difference in the rate of conotruncal CAs ( in the multivitamin group: 2 ventricular septal defects, 1 double outlet right ventricle; in the trace element group: 8 ventricular septal defects, 1 tetralogy of Fallot, 1 complete transposition ) was significant ( c 2 =4.01; p =0.045; relative risk:0.29 CI 95%:0.08,1.05 )

In the final database of the Hungarian intervention trial there was one case with limb deficiency (terminal transverse ) in the multivitamin group and five cases (2 terminal transverse, 2 femur - fibula - ulna complex, 1 split hand and foot ) in the trace element group. (11).The difference is not significant (c 12 = 2.8; p = 0.09 or Fisher p = 0.124 ). These findings were confirmed by US studies published in 1996 and 1997. If we consider the results of the Hungarian trial, periconceptional multivitamin supplementation resulted in 30.8% reduction in the rate of CAs.

In conclusion , in the 1990s there is a breakthrough in the primary prevention of CAs and it is a fantastic result of medical service. However, these finding is a good example to demonstrate that we have a chance to introduce na ew primary preventive method instead of the secondary one, i.e. the termination of pregnancy. Thus we can demonstrate that we do our best to fight against the abortion which is declared by the Catholic Church as a killing of fetuses. The moral-religious and scientific-medical activities can be reconciled and it is good for everybody particularly prospective parents.

References

  1. Smithells RW et al.Vitamin deficiencies and neural tube defects. Arch.Dis. Child 1976;51:944-949.
  2. Smithells RW, Sheppard S, Schorah CJ, Seller MJ, Nevin NC, Harris R. Possible prevention of neural tube defects by periconceptional vitamin supplementation. Lancet 1980; 1: 339-340.
  3. Smithells RW, Sheppard S, Wild J, Schorah CJ. Prevention of neural tube defect recurrences in Yorkshire: final report. Lancet 1989; 2: 498-499.
  4. Nevin NC, Seller MJ. Prevention of neural tube defect recurrences. Lancet 1990; 1: 178-179.
  5. MRC Vitamin Study Research Group. Prevention of neural tube defects: results of the Medical Research Council vitamin study. Lancet 1991; 338: 131-137.
  6. McPartlin J, Halligan A, Scott JM, Darling M, Weir DG. Accelerated folate breakdown in pregnancy. Lancet 1993; 341: 148-149.
  7. Cuskelly GJ, McNulty H, Scott JM. Effect of increasing dietary folate on red-cell folate: implications for prevention of neural-tube defects. Lancet 1996; 347: 657-659.
  8. Canadian Task Force on the Periodic Health Examination, 1994 update 3. Primary and secandery Prevention of neural tube defects. Can Med Assoc J 1994; 151: 21-28.
  9. Czeizel AE. Prevention of congenital abnormalities by periconceptional multivitamin supplementation. Brit Med J 1993; 306: 1645-1648.
  10. Czeizel AE. Reduction of urinary tract and cardiovascular defects by periconceptional multivitamin supplementation. Am J Med Genet 1996; 62: 179-183.
  11. Czeizel AE. Limb-reduction defects and folic acid supplementation. Lancet 1995; 345: 932.

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