THE IMPORTANCE OF THE PROSPECTIVE FATHER

1. The time is ripe for greater attention to fathers' contribution to the outcome of pregnancy. The contribution of fathers varies in a complicated way from one population to the next according to cultural traditions, endemic disease and differences in the habits of men and women. A growing understanding of fathers' role has been one of the changes of the last 30 years. The US Collaborative Perinatal Study 1958-65 of 55,908 women and their pregnancies collected no information on fathers except their incomes. The British Perinatal Mortality Survey 1958 collected no information on fathers except their occupation or social class when available. In response to the growing awareness of the dangers of smoking the German prospective, multi-centre Perinatal Study, 1964-70, included information in the design about fathers' smoking as well as mothers' (Koller, 1983). Details of smoking by fathers were available for 6,714 out of 7,870 pregnancies and about 46 per cent of fathers smoked regularly. This German Study showed that smoking by the father when the mother did not smoke was associated with an increased rate of early and late miscarriage, preterm birth, low birthweight, perinatal death and the occurrence of severe congenital malformations. Figure 9.1 shows from this study a statistically significant association of higher perinatal mortality and fathers smoking. Figure 9.2 shows the association of all severe congenital malformations with father smoking regularly. For every mother who smoked there were 4.2 fathers who smoked and fathers contributed correspondingly more smoking percentage of births with severe malformations Figure 9.2. German multi-centre survey of risk factors in pregnancy: Source: Mau & Netter, 1974, Table 8. Reprinted by permission of Georg Thieme Verlag, Stuttgart. linked malformations. This study suggests that fathers share responsibility with mothers for miscarriage, perinatal death and congenital malformations. Damage to fathers' germ cells, or mutations, are responsible for some part of such unfavourable outcome of pregnancy.

2. Women hoping to have a family at any time should be helped to stop smoking before that time comes. The well-recognized danger of women smoking in pregnancy extends to the prepregnancy period (US Surgeon-General, 1980).

ONE-GENERATION GENETIC DISEASE RESULTING FROM MUTATION IN A PARENT

3. It should be more widely understood that the risk of many one-generation genetic diseases, and indeed diseases inherited by grandchildren, can be reduced by avoiding causes of mutation. These genetic diseases include Down's syndrome and other chromosomal disorders, autosomal dominant disorders like achondroplasia, X-linked disorders like haemophilia, a part of epilepsy, schizophrenia and mental subnormality. Research has continually added to the list of disorders known to be caused in whole or in part by new mutations in germ cells and embryonic cells. This knowledge has increased in step with the increasing understanding of the importance of new mutation in somatic cells in the aetiology of cancer. Research on mutation was motivated from its beginning by concem to protect the human genome and genetic heritage. It only became apparent gradually as research proceeded that much human disease was a consequence of damage to the genome within somatic and germ cells in the not so distant past.

4. Concern should not be limited to protection from mutagens that cause specific, easily identifiable disease but should extend to protection against anything which, like tobacco smoke, increases human mutation rate. Mary Lyon said in Nature in an article entitled: "Measuring mutation in man" (Lyon, 1985):

"Major advances in preventing the birth of genetically affected children are being made, through genetic counselling, prenatal diagnosis and the use of recombinant DNA methods. But mutation remains a problem, resulting in the levels of many genetic diseases being maintained despite adverse selection, and it is becoming increasingly important to assess the possible increase in mutation rates caused by chemical or physical agents in the environment... If the mutation rate rises the incidence of such mutationally maintained diseases will rise, so efforts are being directed towards the detection of mutagens in the environment and their control or elimination."

Mary Lyon then refers to the work of the International Commission for the Protection against Environmental Mutagens and Carcinogens (ICPEMC). There are many chemicals in the environment not yet assessed for mutagenicity.

THE GROWING LIST OF CAUSES OF MUTATION

5. That not only radiation but chemical compounds can cause mutations has been known since the 1930s and 40s (Auerbach & Robson, 1946). Intake of mutagenic xenobiotics is one of the causes of raised human mutation rates. It was in the I 960s that governments world-wide became more concerned about chemical damage to the human genome and the environmental mutagen societies were formed in many countries. The joumal Mutation Research was established in 1964 and one of the early British contributions was about chemtcally induced mutations in mice (Cattanach, 1966a, 1966b, 1982). The domtnant lethal test for mutagenicity using treated male animals and unexposed females was described in 1972 (Epstein & R6hrborn, 1970; Epstein et al., 1972), and has been adopted world-wide (Burger et al., 1989). This test depends upon the capacity of mutagens to cause damage to male sperm. At least 30 chemicals which are mutagenic have been found in tobacco smoke and go far to explain the effects on pregnancy outcome of smoking by fathers and mothers.

6. When prescribing drugs which are known to be mutagenic or which may be mutagenic the possible intention of the patient to start a pregnancy should be considered. There are, of course, circumstances when the prescription of a mutagenic drug, for example morphine, or the use of X-rays are in the best interests of the patients. Couples should confide their intentions, and should when possible postpone onception following the use of mutagenic drugs or X-rays.

7. When possible men and women planning a pregnancy should avoid selftreatment with off-prescription drugs. Drugs reported, often belatedly, to be mutagenic are freely available and sold in substantial quantities in many countries without any weighing of costs and benefits by consumer or supplier. An example is paracetamol reported to be mutagenic in animals and in man (Hongslo et al., 1988; Kocisova et al., 1988). Analgesics have been suggested as an important cause of miscarriage (Watanabe, 1979).

8. Ideally alcohol should not be consumed by men and women hoping to conceive. Alcohol consumption increases the risk of miscarriage (Harlap & Shiono, 1980; Kline et al., 1980). Alcohol affects all levels of the hypothalamic-gonadal axis and can depress levels of gonadotrophins (Gavaler & Van Thiel, 1987). Animal experiments have shown that alcohol interferes with meiosis I and II and can cause chromosomal abnormalities including non-disjunction (Badr & Badr, 1975; Kaufman, 1985). Alcohol consumption is particularly ill-advised around the time of meiosis I and II in men and women (Cicero, 1982). A whole number of Mutation Research in 1987 (volume 183 No. 3) was devoted to papers of the Intemational Commission on the genotoxicity of alcohol (Bridges, 1987).

9. It is wise for men and women to avoid unnecessary consumption of food containing xenobiotic food additives throughout the susceptible periods surrounding conception. Some substances are so widely used as hardly to be thought of as additives. Thus, for example, Arnold & Boyes (1989) have reviewed over 200 papers and the results of over 200 tests on the mutagenicity of saccharin, some negative and some positive. A part of the mutagenicity of commercial saccharin manufactured in Europe, America, Japan, Korea and China has been caused by impurities. It has also been reported that bacteria in the digestive tract cause saccharin to react with amino acids to produce new mutagenic products (Lawrie et al., 1985). The published studies on the mutagenicity, teratogenicity and carcinogenicity of saccharin now cover more than 20 years and show no sign of coming to a conclusion, illustrating the high cost of testing a chemical for mutagenicity when its market is already established and the mutagenicity is challenged. Saccharin is at most a mild mutagen but the mildness may well be offset for the individual who uses saccharin several times a day. About 75 per cent of saccharin production is used in soft drinks and one can may contain 150mg. In 1976 about 3 million kilograms of saccharin were consumed in the USA.

AVOIDING HUMAN CASUALTIES BY USE OF ANIMAL STUDIES

10. Disaster races to meet those who wait for proof of danger. The results of bacterial and animal tests should be respected as there is no other way of avoiding human casualties. DES (diethylstilboestrol) is a drug now known to be mutagenic (Banduhn & Obe, 1985). DES was reported to be carcinogenic in animals in Germany and the USA (Pierson, 1936; Shimkin & Grady, 1940). It was, however, only in 1971 that it was first reported that maternal DES therapy was associated with vaginal adenocarcinoma of their daughters. Claims for damages in the Courts have exceeded $1 billion. This was described in the US Congress as "trial by catastrophe".

11. The Environmental Mutagen Information Centre (EMIC), United Kingdom Office, which operates a computer retrieval service for all mutagens and teratogens should be more widely used (EMIIC-UK). This service is linked to Oak Ridge National Laboratory in the USA. The historical record shows that many casualties caused by mutagenic chemicals and drugs can be attributed to failure to heed published information including the results of animal studies.

12. When no medical cause of miscarriage, or infertility or birth defect can be found chemical mutagens in the work place can be suspected and may be found to be known mutagens. DBCP (dibromo-chioropropane) is a pesticide widely used at one time particularly in Califomia and provides a cautionary tale. DBCP was reported to cause atrophy and degeneration of the testes of rats, guinea pigs and rabbits by Torkelson et al. (1961). DBCP is mutagenic. Sixteen years passed before the first of a long series of papers was published on the impairment of reproductive function, particularly of male workers, engaged in the production or use of DBCP.

13. A prospective father or mother who suspects there may be dangers at work should consult the safety representative of their Trade Union, the personnel department or the medical staff. There are many drugs and chemicals on which EMIIC cannot yet provide adequate information. Employees are also sometimes exposed to mixtures of unknown composition. Safety limits for some mutagens are published but observance of these limits requires measurement in the workplace which is not always done. Furthermore the safety limits which may be acceptable to prevent toxic signs or symptoms in the adult, may not be strict enough to prevent damage to germ cells. The United Kingdom Regulations relating to exposure of employees to lead are, for example, much less strict than the corresponding United States regulations which purport to protect both "males or females who wish to plan pregnancy" (US Department of Labor, 1978). Dangers from some of the commoner chemicals used in industry are discussed by Barlow & Sullivan (1982) and by Fletcher (1985).

THE TEMPORARY DEFERMENT OF CONCEPTION

14. Spacing of births by at least 2 years is wise. Many risks to the following aby increase as the spacing falls below 2 years. At least 15 months from the irth of one child before risking the next conception is a wise rule for couples.

15. A temporary or passing illness of a woman or her partner is a good reason br postponing a conception for 3 or 4 months. Mutation rate is increased by nfectious illness especially by viral disease, and therefore by such temporary, ransient illnesses as influenza and the common cold. Men and women at the time of a conception should try to have been fit and well for a length of time that includes the period of heightened susceptibility of their germ cells. Drugs taken at the time of such temporary illness may also increase mutation rate.

16. Women and their partners with any sign or symptom of chronic illness should confide in their family doctor and should be advised to postpone conception until they have seen a consultant physician. Most of the casualties that might have been avoided by specialist care today, but are not avoided, are the consequence of men and women being referred too late. Thus most of the congenital malformations of children born to diabetic parents can be prevented if the parent or parents are referred to a clinic for careful management of the diabetes well before conception. The same is true of other disorders such as hypothyroidism and some types of anaemia. There is substantial evidence of underdiagnosis of both diabetes and hypothyroidism early enough before conception.

17. Thin women should postpone conception until body weight has been corrected. The 165 women in the Hackney study who had babies in the optimum birthweight range had a mean BMI of 23.7kg/in² (Doyle et al., 1990a). The average BMI is around 24kg/in². The risk of low birthweight, congenital malformation and other handicapping conditions increases as the BMI falls below 24kg/in² and American data show 50 per cent of women infertile below 20.7kg/in² (Frisch, 1977). Experiments in animal husbandry have shown that it is best for fertility and outcome for animals to conceive on a rising and not a falling body weight (Morrow, 1980a, 198Gb).

18. A leaflet for women entitled, Getting Fit for Pregnancy implies that it is wise to postpone a conception until fitness is achieved, and a second, Thinking about a baby? A man's guide to preconception health, implies that a man's health may also be grounds for postponement (Maternity Alliance, 1990). Many family doctors in the British National Health Service give preconception advice or have their own preconception clinics. In Britain there is a series of some 50 clinics in private medicine offering preconception care (Foresight, 1990). A book summarising the advice of these clinics recommends a six month period of improvement in health for men and women in preparation for a conception (Barnes & Bradley, 1990). Such preparation is the most constructive part of family planning and must require postponement of conception, but for widely differing lengths of time.

THE MODULATION OF MUTAGENICITY BY NUTRITION

19. A diet adequate in calcium, magnesium, iron and zinc protects against the heavy metals lead and cadmium. Animal experiments suggest that lead may be the most important mutagen in the contemporary human environment, affecting pregnancy outcome at blood concentrations not infrequently encountered among the less well fed (Wynn & Wynn, 1982). Poor nutrition increases susceptibility in different degrees to most if not 11 mutagens and teratogens and thereby increases mutation rates. Thus well fed rats, for example, tolerate thalidomide (Giroud et al., 1962). However eficiencies of riboflavin, pantothenic acid, folate, cobalamin, tocopherol or itamin A each individually increases the toxicity of thalidomide and makes rats susceptible (Fratta et al., 1965). Poor nutrition increases the half-life of most xenobiotics in the body.

21. Before and around the time of conception it is wise to avoid consuming ood which has been overheated and contains appreciable amounts of the proucts of protein pyrolysis, which include some powerful mutagens that can increase the mutation rate of all body systems.

22. Men planning conception should have a good diet throughout the period of spermatogenesis. A poor diet or reduced food intake resulting from a loss of appetite or otherwise has been shown in animal experiments to increase nutation rate.

23. Women planning pregnancy should have the kind of diet associated with )ptimum birthweight and should avoid the restricted diet associated for example in the Hackney survey with low birthweight as shown in Table 5.6. Poor nutrition is a major risk factor for low birthweight. In the Hackney survey 28 mothers had babies with birthweights 2,500g and below and only one of hese could be described as well fed and she had a low BMI. Now well-fed woman in the Hackney study had a baby who was growth-retarded in utero small-for-dates. A recent paper from Sweden showed that 40 per cent of b1ildren with cerebral palsy had birthweights under 2,500g compared with 4.0 er cent in the general population (Hjalmasson et al., 1988). An earlier Danish ook on spastic cerebral palsy found 39 per cent of children with cerebral palsy had had low birthweights under 2,500g (Glenting, 1970). Papiernik j978) quotes French figures suggesting that over 60 per cent of neurological riandicap is associated with intrauterine growth retardation. In England and Wales 37 per cent of babies notified as having central nervous system malformations weighed under 2,500g at birth (OPCS, 1988). There are many other series showing low birthweight to be an indicator of about one half all congenital neurological handicap. As a corollary it may be inferred that about one hialf all neurological handicap is probably not caused by and is unconnected with maternal nutrition or low birthweight. Animal experiments have shown that mutations in male and female before conception can cause low birthweight and neurological disorders, and many of these mutations have causes unconnected with maternal nutrition.

REVENTING THE REPETITION OF A DISAPPOINTING PREGNANCY

24. Couples anxious to prevent the repetition of a pregnancy which was a disappointment because of a miscarriage, a stillbirth, or because their baby was of low birthweight, needed intensive care or was found to be handicapped, should be a priority for preconception care by the family doctor. A couple who have had a low birthweight baby should be offered nutritional counselling. Advice should be given on adequate spacing of the next pregnancy. A disappointing pregnancy is evidence of risk for any subsequent pregnancy. Following such a sad event a couple should be promised as part of postnatal care that help will be available if they wish to proceed with another pregnancy. Such couples should be referred for obstetric advice, for genetic counselling or to an appropriate specialist department (Chamberlain, 1990). Prepregnancy clinics have been established in London and their practice has been described (Chamberlain & Lumley, 1986). The French Ministry of Health recommended establishing clinics at major hospitals to help couples who have had a disappointing pregnancy (Mahon, 1972).