Care before conception includes care by a couple of themselves and care of a couple by doctors and nurses. What is the evidence that a couple can do things before conception that may improve their chances of having a healthy baby? Does the health of a couple matter before conception? Does the health of a father really affect the outcome of pregnancy? What is meant by the "health" of a couple? Are there hazards in everyday life which may prejudice a couple's chances of having a healthy baby? What is the evidence that there are periods of susceptibility of sperm and ova before and around the time of conception? The answers to these questions assume a greater importance when doctors or nurses advise disappointed couples who fail to conceive, have had a miscarriage or have had a stillbom baby, a baby that required intensive care or a baby with a handicap.

BIRTH-SPACING IS AN EXAMPLE OF PRECONCEPTION CARE

Is "before" conception defined in months even years, in weeks or days or even hours before a conception takes place? One event which indisputably occurs before a conception is a preceding birth. The increase in infant mortality associated with too close birth-spacing is illustrated in Figure 1.1 based on

American data. The British Births Survey 1970 showed that about 13 per cent of low birthweight and perinatal mortality was attributable to too close birthspacing (Chamberlain et al., 1978). The increase in perinatal mortality is illustrated in Figure 1.2. Studies sponsored by the World Health Organization have estimated the infant deaths attributable to birth-spacing under 2 years in some 40 different countries which ranged from 5 to 40 per cent of all infant deaths with an average of about 18 per cent (Maine & McNamara, 1985).

The risk of low birthweight for the following baby also increases as the interval between births is reduced, as illustrated in Figure 1.3 for over one million births recorded in American official statistics. Growth of embryo and fetus is a result of cell replication and low birthweight is a consequence of a reduced rate of cell replication, except in those cases when late in pregnancy the baby is bom too soon. If embryonic cell replication rate falls there is an increased risk of congenital malformations caused by what has been described as "asynchronous differential growth" (Eckhert & Hurley, 1977). Too close birth-spacing increases the risk of congenital malformations as illustrated in Figure 1.4 for mental defects, In this Australian study by Field and Kerr (1981) there were 80 cases of anencephalis or meningomyelocele of which 29, or 36 per cnet, wre born less than one year after the previous birth, whil only 4 or 5, or about 6 per cent, would have beeb expected if close birth-spacing had not increased the risk. Too close birgth spacing can therefore produce a condition in the mother that results in a slow-down in cell replication very early in the next pregnancy.

In his introduction to a manual on prepregnancy care of women Chamberlain (1986) describes the two components of care: The larger is the appropriate and desirable knowledge for young people which is part of health education which is in turn part of education for living; the smaller component is medical and is concerned with identifiable problems meriting treatment. The knowledge that there is a desirable birth-spacing of 2 to 4 years and that birth-spacing under 2 years is unwise belongs to appropriate knowledge for all young people. The most important conclusions in the present book are all such appropriate parts of health education rather than conclusions about the treatment of patients. Conclusions like the desirability of adequate birth-spacing are generally simple, but the supporting evidence necessary to convince doctors, nurses and parents is often far from simple; only world-wide studies sponsored by the World Health Organization have made it clear how serious the contribution of too close birth-spacing is to reproductive casualties and, indeed, years after wards to small size and poor performance at school (Martin, 1978).

Some understanding of the concept of risk is a necessary part of the education of all young people and couples if they are to look after their own health. Close birth-spacing does not, of course, inevitably cause disaster but increases the risks. There is no certainty but only an increase in risks as birth-spacing is reduced as shown in Figures 1 to 4. Preconception care, and indeed most of preventive medicine, is concerned with reducing risks. The risks of an unfavourable pregnancy outcome cannot be reduced to zero but only ever to a level which is a best possible for a particular couple. It is noteworthy that satisfactory pregnancy spacing depends upon action by the couple themselves and the role of the health professional is that of conveying the knowledge that risks increase progressively as spacing is reduced below 2 years. Many parents of more than one child will tell you that they were told nothing by the health services about the importance of birth-spacing.

LOW BIRTHWEIGHT IS AN INDICATOR OF RISK

The appropriate knowledge for disappointed couples who fail to conceive, have miscarriages, stillborn, frail or handicapped children is more extensive than the knowledge appropriate for all young people. Such couples are concerned to prevent a repetition. The writers when visiting a neonatal intensive care unit met a young mother visiting her second low birthweight baby in an incubator. This young mother had been given no advice whatever between pregnancies on how to reduce the risk of a recurrence. The staff of the maternity hospital where both babies were born, general practitioner, community midwife or health visitor had all said nothing after the first pregnancy about timing of the second pregnancy or about the many other ways of reducing the risks of low birthweight discussed in the present book.

Too close birth-spacing is only one of many causes of slow-down of embryonic cell replication, low birthweight of embryonic origin and congenital malformation. The association of congenital malformation and low birthweight is general as illustrated from the statistics from England and Wales in Figure 1.5 for neural tube defects and Figure 1.6 for heart defects. The congenitally malformed heart has cells normal in size but generally reduced in number (Cheek et al., 1966). Low birthweight has been reported to increase the risk in the adult later in life of ischaemic heart disease and raised blood pressure (Barker & Osmund, 1986; Barker et al., 1989; Whincup et al., 1989).

The normal rate of cell replication during embryonic development is very much higher than later in pregnancy. Low birthweight matters most when it is associated with malformation and maldevelopment of early origin, at the time when cells are differentiating as well as dividing. The mass of the zygote after conception is about 4 micrograms but the foetus reaches 14-grams at the end of the first trimester. The mass has to double about 22 times between conception and the end of the first trimester, but the mass then only doubles 8 times until the end of pregnancy to reach 3,500g. In fact the zygote before first cleavage is more than 1,000 times larger than the average cell of the foetus at the end of the first trimester. The zygote requires at least another 10 doublings to reduce the cell size so that total doublings during the first trimester are more than 32 without allowing for cell death. Early cell replication is part of a genetically determined program and if part of the program is omitted it cannot be reinstated later, any more than it is possible for an actor to reinstate lines of a play in the third Act that he accidentally omitted from the first. Most congenital malformations may be regarded as the result of omissions of part of the genetic program of cell replication. The risk of such omissions increases if the rate of cell replication slows down below the programmed rate.

Congenital mafformations and low birthweight may be caused by insults during early pregnancy to the developing embryo and they may also be caused by insults to germ cells before conception. It may then be asked whether too close birth-spacing damages the female germ cell or ovum before conception. The answer to this question is to be found by studying miscarriage, particularly early miscarriage which is the commonest form of pregnancy failure. The risk of miscarriage in a second pregnancy increases as the birth interval falls below 2 years as illustrated in Figure 1.7 based on a study sponsored by WHO of pregnancies in Ankara, Turkey (Omran & Standley, 1976).

Several studies have shown that more than one half all miscarried embryos have chromosomal abnormalities. Thus a study at the University of British Columbia of 228 em bryos aborted found that 129 or 57 per cent, had chromosomal abnormalities (Poland e2t al., 1981). What then is the origin of these chromosomal abnor malities? Such abnormalities are defects in the genome, and therefore must have their origin before or sometimes around conception. The origin of defects in female germ cell or ovum is discussed further in Chapter Two and in male germ cell or sperm in Chapter Three.

ONE-GENERATION GENETIC DISEASE

Concern at the apparently growing number of causes of damage to germ cells in our complex urban world persuaded leading countries to establish "envi ronmental mutagen societies" about 1960. A report of the European society defined a "mutation" very broadly as "an alteration in the genetic apparatus of an organism" (European Environmental Mutagen Society, 1978). More than half of all early miscarriages are by this definition caused by mutations. Fur thermore by this definition too close birth-spacing causes mutation in maternal cells. The intemational body of national environmental mutagen societies pub lished a report on estimation of the diseases caused by new mutations in man and said (ICPEMC, 1983):

"Mutagenic agents may cause genetic damage in any cell of the body. If the damage occurs in somatic cells it may lead to cancer, or other degenerative diseases in the exposed individual. In a somatic cell of a foetus such genetic damage may result in congenital abnormality. However, if the damage occurs in a germ cell, it may be transmitted to the next or later generations where it may cause disease."

This quotation refers to the foetus and includes the early or embryonic period of two months after conception when the genetic apparatus of the dividing and differentiating somatic cells of the embryo is particularly susceptible to damage.

Because the cause of some disorder is environmental the origin is not necessarily postconceptional. An environmental factor may cause a mutation in a germ cell. Such a mutation is an event before conception. Research over many years has shown that there are numerous environmental causes of mutation including radiation and many chemicals, and rates of mutation are modulated by acidity, alkalinity, temperature, intracellular concentrations of hormones and nutrients and viral diseases. Because the cause of some disorder is "genetic" it is not necessarily inherited from grandparents because it may be mutational in origin. A disorder that is inherited may not be inherited from grandparents or more distant ancestors but only from parents whose germ cells acquired a mutation. Such a disorder may be called a one-generation genetic disease.

Some serious disorders are inherited from parents but are not compatible with reproduction and sufferers have no descendants yet the disease persists in the general population. Down's syndrome is such a disorder. Only 24 women with Down's syndrome have been reported to have had a child, and no men with Down's syndrome to have done so (Jagiello, 1981). Down's syndrome is genetic and inherited; sufferers have an extra chromosome 21. But Down's syndrome is not inherited from grandparents except in perhaps 5 per cent of cases where there is a predisposing mosaicism2 or a translocation, which may be acquired from grandparents. Down's syndrome is an example of a one-generation genetic disease caused by mutations in parental germ cells. The prevalence of Down's syndrome in the community is almost wholly main-tamed by new mutations in parental germ cells at times discussed in later chapters. A report on estimation of diseases caused by new mutations in man by ICPEMC (1983) concluded:

"Thus, in man mutation must be considered essentially harmful. In addition, the harmfulness of mutation can be seen from the fact that a variety of diseases depends on repeated mutation for their continued presence in the population."

"Thus natural selection tends to eliminate the genes or chromosome changes concerned from the population and the incidence of the conditions depends upon a balance between selection, tending to decrease the incidence, and new mutations, tending to increase it. Thus, an increase in the rate of mutation will raise the incidence."

The fertility of sufferers from Down's syndrome is virtually zero so that the incidence is proportional to the rate of mutation. The report refers to epilepsy, schizophrenia, many kinds of congenital malformation, diabetes and many other disorders as partly genetic in origin with a depressed fertility of sufferers and with a prevalence partly maintained by new mutations.

NEW MUTATIONS ARE A CAUSE OF HANDICAP

The decline in infant and perinatal mortality over the last half century has not been matched by a decline in birth defects. The US Centers for Disease Control (1989) say that the USA will not reach its national target for lowering infant mortality because birth defects are not falling. The prevention of undesirable mutations is an essential part of programs aimed at preventing birth defects and handicap. Undesirable mutations are a cause not only of physical defects which are apparent at birth but also of defects with no obvious dysmorphology. Mutations are, in particular, responsible for a range of defects of the central nervous system which are among the most serious human burdens. Studies in Britain, Sweden, Germany and44 elsewhere have shown that psychiatric patients are subfertile (Slater et al., 1971; Larsen & Nyman, 1973). The lower marriage rate and the lower fertility of those who marry reduces fertility to approximately one half that of the general population, so that prevalence would fall by about 50 per cent per generation if it depended only on the reproduction of psychiatric patients and upon them all having abnormal children. However the very great majority of psychiatric patients have normal parents and the prevalence of psychiatric disorders is not falling.

The fragile-X syndrome is the commonest cause of mental subnormality in men after Down's syndrome (Moser, 1985). Fragile sites or break-points in chromosomes, of which some 30 or 40 including the fragile-X site have been identified, are associated with an increased risk of miscarriage and stillbirth (Hecht & Hecht, 1984). The clinical significance otherwise of most fragile sites is not known execpt for the site on the X-chromosome at Xq27 associated with mental subnormality in the male. Sutherland, who was a pioneer in the discovery of the fragile-X syndrome, studied 104 cases from 95 unrelated families and concluded that the syndrome was the result of new mutations (Mulley & Sutherland, 1983). Mothers can be carriers of the fragile-X syndrome, but are only slightly affected if affected at all, and can transmit the mutation from a grandfather. Sutherland found that the sufferers were almost all infertile, but the syndrome is constantly regenerated from mutations in father, mother, grandfather and exceptionally in more remote forebears (Winter, 1987). The fragile-X syndrome is an exception to a general association of mental subnormality and small size.

Epilepsy is another example of a disease which is partly caused by one- generational genetic inheritance. A study of 274 pairs of identical twins found that when one twin had epilepsy so had the other in 57 per cent of cases, while in 570 pairs of non-identical twins the concordance was only 11 per cent as shown in Table 1.1 (Tsuboi & Endo, 1977). These twin studies suggest that the genetic contribution to the prevalence of epilepsy is around 50 per cent. However averaging the results of 7 studies of 6,822 epileptic parents the risk of a child being epileptic if only one parent was epileptic was only 3.5 per cent as shown in Table 14.2 (Janz et al., 1982). A study from Montreal found that young men and women with epilepsy particularly young men, have lower marriage rates than normal and only about half the average number of

TABLE 1.1

TWIN STUDIES OF EPILEPSY

	one epileptic	both epileptic	concordance per cent
monozygotic twins	119	155	57
dizygotic twins	509	61	11

Source: Tsuboi & Endo,1977; summary of 17 series, 844 sets of twins.

children (Dansky et al., 1980). Combining the effects of lower fertility and risk of inheritance from an epileptic parent it is found that less than 2 per cent of epileptics have epileptic parents. Ninety-eight per cent of epileptics are born to parents with no family history of epilepsy. Epilepsy is continually dying out but is continually regenerated partly by new mutations in parental germ cells and partly by insults after conception and after birth. Low birth-weight and small head circumference are both risk factors for many brain disorders including epilepsy. A series of 265 patients with congenital cerebral palsy in a Danish study included 81 who had single convulsions or epilepsy. Twenty-six per cent of the epileptic patients had birthweights under 2,500g (Glenting, 1970).

TABLE 1.2

CHILDREN WITH ONE EPILEPTIC PARENT WHO HAVE EPILEPSY

number of couples (one epileptic):	6,822
number of their children:	5,357
number of children with epilepsy:	188 or 3.5 per cent

Source: Janz et al., 1982; summary of 7 studies

Smaller size is not necessarily evidence of lower intelligence. The Shire horse is not more intelligent than the Shetland pony, and elephants are not more intelligent than people. If small size is part of normal genetic programming it has no such direct connection with mental performance. If however, small size is a consequence of slow-down in embryonic growth there is an increased risk of educational subnormality. Studies of American children in the 1940s reported "an unexpectedly high relation between intelligence quotients and stature" (Boas, 1941). A study of children attending English special schools for the educationally subnormal reported that these children were also physically backward with average heights and weights substantially below the average (Parry-Jones & Murray, 1958). There was a debate on whether the unusually small children at these special schools were "an expression of man's genetic variability" or were small because of inadequacy of the home environment. These are not the only two alternatives.

Growth retardation or small size may begin with mutation in the germ cells of mother or father as well as in remote ancestors, or at any time after conception during the development of the zygote or embryo. Small size at birth may or may not be wholly or partially corrected by subsequent catch-up. But if the newbom is small for gestational age and there is no subsequent catch-up there is cause for concern. There is a risk of educational subnormality if head circ0umference at birth is below the 10th percentile and remains below the 10th percentile in early childhood (Dunn et al., 1986)

Educational subnormality has many postnatal causes, is difficult to measure and however measured has a continuous scale extending from normality to extreme forms of handicap. The cases of only slight or moderate degrees of mental handicap often of postnatal origin are umerically and therefore socially of greater importance than the small number of serious cases requiring long-term hospital care. However, the origin of much mental handicap can be seen more clearly by study of the more serious cases. There is just one physical characteristic that the majority of the severely mentally subnormal have in common. They are very little people and in particular have small heads. The cranial volumes of 358 severely subnormal patients at the Rinnekoti Institute in Finland are shown in Figure 1.8 (Iivanainen, 1974). The cranial volumes

of 207 patients were below the 5th percentile, that is 74 per cent of the total, while only 10 patients had cranial volumes above the 95th percentile. About 95 per cent of the 358 patients were below the 50th percentile of height for age and 180 or over one half were below the 2.5 percentile. At some stage in their development these little people had suffered a slow-down in cell replication. In 18 per cent of cases there was evidence of postnatal trauma or infection and in a further 12 per cent of cases there was evidence of trauma or hypoxia or other perinatal cause of the handicap. In 69 per cent of cases there was some malformation of the skull, as well as small skull volume, a combination likely to have its origin in early pregnancy or earlier still. Growth retardation of the head is more closely associated with neurological deficits than growth retardation of the rest of the body as commonsense would anticipate (Gross et al., 1978; Nelson & Deutschberger, 1970). The US Collaborative Perinatal Study provided information on the children found to be neurologically abnormal at one year of age on 31,240 children. The risk of neurological abnormality for infants with birthweights under 2,500g was 3.35 times that of the infants who had higher birthweights (Niswander & Gordon, 1972).

SUSCEPTIBILITY OF GERM-CELL STAGES

If an important part of all handicap has its origin very early in pregnancy the only hope of primary prevention must depend upon intervention before conception. If, furthermore, embryonic development is prejudiced by mutations before conception then preconception care is also indicated. The period before conception when germ cells are particularly susceptible to mutagens does however need to be defined. In animals the risk of some particular insults causing a subsequent pregnancy failure by damaging germ cells has been reported to increase during the prepregnancy period by a 1,000 times or more (Adler, 1982a). There are periods of heightened susceptibility to mutagens extending forward into the embryonic period and backward into the period of maturation of germ cells. These periods of heightened susceptibility differ for different mutagenic agents, for different types of mutation, and for men and women (Lyon, 1988).

In 1981 Mary Lyon of the Medical Research Council, Radiobiology Unit, Harwell presented a paper to the International Commission entitled Sensitivity of various germ-cell stages to environmental mutagens. Among the conclusions the pape1r said:

"In instances in which exposure is not continuous but occasional it may be possible to remove a large part of the genetic hazard by avoiding conception for a few months after exposure. Such cases might include accidental exposure, or some types of medical treatment."

This was among the first papers to underline the importance of the preconception period for the prevention of mutations and genetic damage.

The final report of the Intemational Commission under the Chairmanship of Mary Lyon concluded (ICPEMC, 1983):

"It may be particularly important to know the risk to maturing stages of germ cells, since it may be possible to avoid the genetic harm done to these stages, if the accidentally exposed individuals refrain from conception for 3 months."

The period of heightened susceptibility for women is discussed in Chapter Two and for men in Chapter Three. In both these chapters the causes of damage to germ cells and embryo are chosen for the light that they throw on these susceptible periods rather than for their common occurrence. Counselling to reduce the risk of handing on recessive disorders to the next generation is outside the scope of this book. Evidence is, however, introduced aimed at reducing genetic harm caused by new mutations.