The importance of nutrition around the time of conception in the prevention of handicap

Epidemics of congenital malformations

Many epidemics of congenital malformations or birth defects were reported in the medical journals of continental Europe following the last war. These epidemics were attributed to food shortage. A bibliographical note is at the end of this paper. The post-war epidemic in Hungary recorded at the Debrecen teaching hospital is shown in Fig. 1 (Nagy et al., 1961). The records of this Hungarian epidemic show that the frequency of many different kinds of malformations increased at the height of the epidemic.

The major congenital malformations originate not later than the period of organogenesis or embryogenesis, defined as including the first eight weeks of pregnancy. One of the papers that recorded the post-war epidemic in Berlin concluded (Kuhnelt & Rotter-Pool, 1955): "We must be concerned in future with the optimal and in every sense adequate nutrition during the first weeks of pregnancy (and not as hitherto with the last weeks of pregnancy)".

Poor nutrition is much more damaging to the outcome of pregnancy around the time of conception than subsequently. This is illustrated in Fig. 2 showing the perinatal mortality of babies born and conceived through the food shortage in parts of Holland from October 1944 to May 1945. This food shortage was painstakingly documented by an American team (Stein et al., 1975). It is seen that the big increase in perinatal mortality by over 100 per cent was not among the babies born during the food shortage but among babies born nine months later who had been conceived during the food shortage.

Table 1. Deaths under one year from malformations of the central nervous system of babies born before the Dutch hunger winter 1944-5 and babies conceived during and immediately after the food shortage. Based on data in Stein etaL (1975) pp. 188-91.

Table 2. Deaths under one year from 91other malformations92 of babies born before the Dutch hunger winter 1944-5 and babies conceived during and immediately after the food shortage. Based on data from Stein etaL (1975) pp. 188-91.

The big increase in perinatal daths nine months after the food shortage was caused partly by congenital malformations which increased in prevalence by 100 per cent as shown in Tables 1 and 2. These tables show that the epidemics of malformations continued for four months, and indeed longer for "other" malformations, among babies conceived after the food - shortage came to an end in May 1945. In effect it took women four months to recover their normal reproductive health. This delay in complete recovery from malnutrition is important because it may be inferred that every woman with a poor nutritional status needs this time to acquire a good status and reproductive health. The four months points to the length of preconceptual care that may often be needed.

The European food shortages caused casualties both early and late in pregnancy. Deaths attributed to "prematurity", which meant low birth weight, are shown through the Dutch hunger winter in Fig. 3. Malnutrition late in pregnancy resulted in babies born with poor vitality, lacking in fat stores and with impaired immune systems, causing a higher death-rate from infection illustrated in Fig. 4. In times of food shortage infections flourish and babies born during the food shortage were more exposed to infection. However, there is now a substantial body of research showing that babies malnourished in utero have a depressed immune competence and lower resistance to infection (Chandra & Newberne, 1977). There was little evidence that those babies whose mothers were exposed to the Dutch food short-age late in pregnancy suffered much disability if they recovered. It must be remembered that the babies in Fig. 3 who died during the food shortage were born into very difficult circumstances. In contrast the babies conceived during the food shortage were born in peacetime, when the Allies had fully restored food supplies, to mothers who were generally well fed, but died in larger numbers nevertheless. It was, furthermore, the babies conceived during the food shortage who suffered from a range of disabilities as illustrated in Tables 1 and 2.

The association of infertility and congenital malformations

A food shortage causes not only an epidemic of congenital malformations and low birth-weight nine months later, but also an epidemic of infertility. During the last four months of the Dutch hunger winter the number of babies conceived fell to only 51 per cent of the previous conception rate, as judged by the number of births subsequently (Stein et al., 1975). The same thing happened in other cities, for example in Frankfurt the birthrate fell to under 30 per cent of the previous level during 1944 and 1945 (Naujoks, 1949). Present-day studies of infertility show that if a woman's weight is reduced, for example by slimming, a point is always reached when she becomes amenorrhoeic and infertile (Crisp, 1978; Fries, 1974; Frisch, 1977). Humans, in common with all other mammals, have a 0nutritionally-determined infertility threshold. During a food shortage women belong to one of three categories: they may be infertile and amenorrhoeic; they may be still well enough fed to have healthy babies; or they may be in a zone in which they are just fertile but produce growth-retarded or malformed babies. These three zones are shown diagrammatically in Fig. 5. We call the zone between infertility and normal reproduction the penumbral zone or the penumbra. This is a zone of enhanced risk of a slowdown in rates of DNA synthesis and embryonic cell replication. Nutrition in the penumbra is marginally inadequate, but is not grossly deficient, for this would cause infertility.

Research into the effect of nutrition and body weight on the age of menarche and the treatment of anorexia nervosa have produced a substantial literature on the relationship of bodyweight and amenorrhoea. The point of onset of amenorrhoea, which is approximately the same point as the infertility threshold, expressed in terms of women's body weight, is shown in Table 3 as reported from three countries. Women's weight reflects calorie balance during the months preceding measurement. If body stores of fat fall below about 12 kg the endocrine system fails to maintain the menstrual cycle (Frisch, 1977). The risk of handicap of early pregnancy origin increases as the infertility threshold is approached (Wynn & Wynn, 1981).

The association of low prepregnancy weight and handicap

The forms of handicap originating in what we have called the penumbra are not limited to congenital malformations. A Swedish paper (Bjerre & Bjerre, 1976) by the head of the obstetric department of Malmo General Hospital and his wife, a paediatrician and head of the assessment centre for handicapped children, shows the handicap diagnosed at age five among 161 singleton babies who were all born of low birthweight. The results are summarised in Table 5; but Table 4 shows first of all the prepregnancy weight of the mothers compared with average weight of Swedish women at the infertility threshold. It was seen in Table 3 that the British mean prepregnancy weight at the infertility threshold was 53 kg; it is seen that the mean weight of the Swedish mothers of low-birth-weight and handicapped children was only marginally higher than this. It is seen in Table 4 that the women who produced these 161 low-birth-weight babies had an average prepregnancy weight between 53 and 54 kg or only one or two kilograms above the Swedish infertility threshold of 52 kg (Table 3), showing the increased risk of low birth weight as the infertility threshold is approached. The

161 singleton low-birth-weight babies included nine babies who were malformed, including one case of spina bifida and hydrocephalus who survived to age five. These 161 babies also included many others who were handicapped as seen in Table 5. Not only the risks of low birth weight and congenital malformations, but the risk of cerebral palsy and other neurological disorders, is seen from Tables 4 0 and 5 to increase as the infertility threshold is approached. The incidence of death and neurological abnormality in Table 5 is more than 20 times that found in the average Swedish population of fully grown babies. The associations of low prepregnancy weight also include much reproductive illness of the mothers as well as handicap in the babies. In this Swedish series the mothers of low-birth-weight babies, including those born at full term, had much more bleeding during pregnancy, more toxaemia and also more infectious illness suggesting a depressed immune status.

Table 5. Low-birth-weight babies examined at age five for neurological status: Sweden, 1976, singletons only (Bjerre & Bjerre, 1976)

Dead	28
Cerebral palsy	5
Delayed motor maturation	31
Minimal brain dysfunction	10
Spina bifida	1
Normal	71
Not examined	15
Total	161

An American study (Niswander & Jackson, 1974) of 32 different factors affecting birth weight found that maternal prepregnancy weight was the most important single correlate of birth weight as illustrated in Table 6. Many other factors are correlated with maternal weight, height and birthweight, but after adjusting the correlations for 29 other factors the authors concluded: "The influence of maternal height on birth weight remains small, while that of prepregnant weight and maternal weight gain persists at the highest levels of importance."

Not only is weight much more important than height as a determinant of birth weight but height reflects nutrition in the more distant past and is partly intergenerational, while prepregnancy weight reflects calorie balance during the months preceding pregnancy and is much more important for preventive medicine because it can be changed. There are now American, Canadian, French, German and Swedish studies showing the association of low prepregnancy weight with low birth weight, mortality and handicap. It was seen in Table 3 that some 10 per cent of women are still fertile at body weights as low as 47 kg for average height and 10 per cent of women are infertile at body weights as high as 59 kg. This variability, and the partial correlation coefficients of 0.26 and 0.29 seen in Table 6, suggest that there are factors influencing both fertility and low birth weight other than maternal weight or calorie balance.

Research on farm animals has shown that infertility can be caused by a deficiency of protein or of one or more of a range of micronutrients (Morrow, 1980). Experiments on laboratory animals have been in progress for over 40 years and have also shown that infertility can be caused by many different nutrient deficiencies and that the risk of malformations, growth retardation and other fetal disorders increases as the supply of some nutrients, notably the B vitamins and some minerals like zinc, is reduced and as the infertility threshold is approached (Warkany, 1971; Tuchmann-Duplessis, 1977; Fratta, Sigg & Maiorana, 1965). This experience with many kinds of animals is a warning that low calorie intake is probably only an aggravating factor in the multifactorial causation of human infertility, congenital malformations and neurological disorders and that, furthermore, the quality of nutrition around the time of conception may well be more important than calorie intake.

Reports have been published of two trials, in Leeds and in South Wales, of nutritional intervention before conception and in early pregnancy (Smithells et at., 1980; Laurence et at., 1980).

In the Leeds study patients and controls were all women who had had a child with a mal-. formation of the central nervous system previously, and expected prevalence in the absence of intervention was about 5 per cent. The study patients were given a multivitamin and iron preparation (Pregnavite Forte F, Bencard), one tablet three times a day for not less than 28 days before conception. The outcome for study mothers is contrasted with the mothers who took no supplement in Table 7. It cannot be assumed that the significant reduction in malformations was attributable only to vitamins because many of the mothers must have been aware that it was thought by the organisers that malformations were at least partly caused by poor diet and many must have tried in other ways to improve their diets.

Table 7. Possible prevention of CNS malformations by periconceptual vitamin supplementation: Great Britain, 1980 (Smithells et al, 1980)

	Number of infants/fetuses
	Without CNS malformations	With CNS malformations
Supplemented mothers	178	1 (0.6%)
Non-supplemented mothers	260	13 (5.0%)
p < 0.01

In the South Wales trial 103/186 women were given dietary counselling in-between pregnancies and 78/103 improved their diets. In this study also patients and controls had previously had a child with a CNS malformation. The very significant association of both spontaneous abortion and CNS malformations with a poor diet is apparent in Table 8.

Table 8. Association of poor diet, spontaneous abortion and malformations: South Wales, 1980 (Laurence et al, 1980)

	Quality of diets
	Good	Fair numbers	Poor	Significance of difference
Normal births	53	85	22
Spontaneous abortions	zero	3	15	p < 0.001
Central nervous system malformations	zero	zero	8	p < 0.001

Much handicap originates during the weeks around conception, not only visible malfor mations of the skeleton but a proportion of all cases of low birth weight, cerebral palsy, mental subnormality and minimum brain dysfunction. Self-care must be preceded by an awareness of the importance of diet during the months before conception. The dietitian can do much to prevent handicap by increasing this awareness among young people including older school children.

Bibliographical note.
Epidemics of congenital malformations in Europe during and after the war 193945 associated with food shortage. The following papers are selected for accessibility and interest; all include numerical data from particular hospitals or regions listed in alphabetical order:

Kovacs, I. & Makay, L. (1960): Zur Frage der Atiologie derMiss bildungen. Zbl. Gynakol. 82, 1335.

Berlin

Eichmann, E. & Gesenius, H. (1952): Die Missgeburtenzunahme in Berlin und Umgebung in den Nachkgriegsjahren. Arch. Gynakol. 181, 168.

Kuhnelt, Hj. & Rotter-Pool, P. (1955): Die Missbildungen an der Universitats-Frauenklinik Berlin im Spiegel der Embryopathologie. Zbl. Gynak ci. 77, 893.

Winter, G.F. & Patz, A. (1958): Die Missbildungshaufigkeit in Berlin und Umgebung in den Jahren 1950-56. Arch. Gynakol. 190, 404.

Chemnitz

Novak,J. (1950): Haufigkeit der Missbeburten in der Nachkriegsjahren 1945-9. Zbl. Gynakol. 72, 1313.

Debrecen

Nagy,T., Bazso,J. & Lampe, L. (1961): Haufigkeit derMissbildungen im Krankengut unserer Klinik. Zbl. Gynakol. 83, 866.

Dresden

Hohlbein, R. (1959): Missbildungsfrequenz in Dresden. Zbl. GynakoL 81, 719.

Hohibein, R. (1952): Missbildungshaufungund Umweltseinflusse.Dt Gesd. lVes. 13, 281.

Erlangen

Thomas, J. (1960): Der heutige Stand unserer Kenntnisse uber Entstehung und Vorkommen menschlicher Missbildungen. Zbl. Gynakol. 82, 1417.

Frankfurt

Naujoks, H. (1949): Kriegs-und Nachkriegsopfer der Frau. Dtsch. med. Wschr. 74, 393.

Leipzig

Aresin, N. & Sommer, H.K. (1950): Missbildungen and Umweltfaktoren. Zbl. Gynakol. 72, 1325.

Canzler, E., Funk, G. & Schlegel, L. (1969): Die Missbildungshaufigkeit an der Universitats-Frauenklinik Leipzig in den Jahren 1941 bis 1965. Zbl. Gynakol. 91, 833.

Munich

Kiebanow, D. & Hegnauer, H. (1951): Zur Frage der sekundaren germanitiven Ovarialinsuffizienz. ZbL Gynakol. 73, 50.

Rome

Picciani, V. (1955): Deficiente alimentazione materna e malconformaziom congenite fetali. Gun. Ostet. Ginec. 57, 24.

Wurzburg

Gotz, F. (1960): Zur Frage der Fehlbildung.Med. Kim. 55, 577.
A discussion with diagrams and numerical data of the epidemics of congenital malformations associated with post-war and wartime food shortages in Berlin, Dresden, Leipzig and Holland is given in Wynn, M. & Wynn, A. (1979): Prevention of handicap and the health of women (Routledge and Kegan Paul, chapter 2) and in Prevention of handicap of early pregnancy origin (Foundation for Education and Research in ChildBearing).

References (See also Bibliographical note)

Bjerre, B. & Bjerre, I. (1976): Significance of obstetric factors in prognosis of low birthweight children. Acta Paediatr. Scand. 65, 544-56.

Chandra, R.K. & Newbeme, P.M. (1977): Nutrition, immunity and infection. New York: Plenum Press.

Crisp, A.H. (1978): Psychopathology of weight-related amenorrhoea. In Advances in gynaecological et.locrinology. London: Royal College of Obstetricians and Gynaccologists.

Fratta, I.D., Sigg, E.B. & Maiorana, K. (1965): Teratogenic effect of thalidomide in rabbits, rats, hamsters and mice. Toxicol. Appl..Pharmacol. 7, 268-86.

Fries, H. (1974): Secondary amenorrhoea, self-induced weight reduction and anorexia nervosa. Acta Psychiat. Scand. Suppl, 248.

Frisch, R.E. (1977): Food intake, fatness and reproductive ability. In Anorexia nervosa, ed R.A. Vigersky. New York: Raven Press. Health Education Council (1980): Looking after yourself. London: HEC.

Laurence, K.M., James, N., Miller, M. & Campbell, H. (1980): Increased risk of recurrence of pregnancies complicated by neural tube defects in mothers receiving poor diets and possible benefit of dietary coun selling. Br. Med. J. 281, 1592-4.

Lindberg, W., Natvig, H., Rygh, A. & Svendsen, K. (1956): H~yde-og vektunders0kelser hos voksne menn og kvinner. Tids. Norske Laegeforening 11,361-8.

Morrow, D.A. (1980): Nutrition and fertility in dairy cattle. Mod. Vet. Pract. 61, 499-503.

Niswander, K. & Jackson, E.C. (1974): Physical characteristics of the gravida and their association with birthweight and perinatal death. Am. J. Obstet. Gynecol. 119, 306-13.

Smithells, R.W. & Sheppard, S. et al. (1980): Possible prevention of neural tube defects by periconceptual vitamin supplementation. Lan cet 1, 339-340.

Stein, Z., Susser, M., Saenger, G. & Marolla, F. (1975): Famine and human development: the Dutch hunger winter, 1944-5. Oxford: Oxford University Press.

Tuchmann-Duplessis, H. (1977): Drug effects on the fetus. New York, Auckland: ADIS Press.

Warkany, J. (1971): Congenital malformations. New York: Year Book Medical Publishers.

Wynn,M. & Wynn, A. (1981): Prevention of handicap of early pregnancy origin. London: Foundation for Education and Research in Child-Bearing.