7. Infectious illness before conception

THE CASE FOR AVOIDING CONCEPTION DURING INFECTIOUS ILLNESS

That herpes virus can cause visible damage to chromosomes was first reported in Nature by Hampar and Ellison in 1961. Since that time many other viruses have been shown to be mutagenic and it was suggested in Mutation Research in 1986 that all viruses are mutagenic and that they are a significant cause of inherited congenital defects in man (Gershenson, 1986). Some other microorganisms including the rickettsiae and mycoplasmas, that spend part of their life cycle within cells, are another ubiquitous cause of mutation (Halkka & Halkka, 1969; Kundsin et al., 1971). In populations in which the adults lack immunity to viral diseases such as measles, mumps and chicken pox they have dramatic effects on reproduction. For example measles and influenza epidemics on Pacific islands have been reported to reduce birth-rate by 80 per cent 9 months after the epidemic (Smith, 1960). Numbers of men and women still reach reproductive years without immunity to chicken pox, measles, mumps and whooping cough in the United Kingdom in spite of immunisation of children. These childhood fevers can cause congenital malformation and stillbirth (Hurley, 1983). Figure 7.1 shows the rise and fall in mutation rates as indicated by chromosomal breaks in cultured leucocytes following the onset of infection (Aula, 1965).

The damage done to the male germ cells of mice by influenza virus in the laboratory is illustrated in Figure 7.2. Most early miscarriages are a consequence of mutations of parental germ cells, as shown in Chapter Two from the study of early abortuses. Aneuploidy is the commonest type of mutation associated with early miscarriage, which is perhaps the commonest outcome of a mutation before and around conception. It would therefore be expected that viral diseases which are mutagenic would cause miscarriage. The literature of centuries states that this is indeed so. Finland (1973) quoted Hippocrates " first treatise on "Epidemic Diseases" describing the effects of influenza: "All my acquaintances miscarried that chanced to be with child". The long history of influenza is marked by great differences in the apparent potency of the virus and in the susceptibility of populations and individuals. Miscarriage was reported in 25 to 40 per cent of pregnancies during the 1918 influenza pandemic in the USA and the case-fatality rate of pregnant women averaged about 10 per cent (Harris, 1919). In contrast the Asian influenza epidemic in the autumn of 1957 caused very few casualties among pregnant women, but a study at the Johns Hopkins Hospital, Baltimore, showed that among serologi cally confirmed cases of influenza during the first trimester of pregnancy there was a significant increase in casualties notably of miscarriages and births with congenital malformations (Hardy et al., 1961).

The history of most diseases shows great contrast between their impact on different populations. In one report from Saudi Arabia 35 per cent of pregnancies complicated by hepatitis ended in miscarriage or stillbirth and there was a high mortality among the pregnant women (Gelpi, 1970). Well-fed pregnant women in Munich apparently infected by the same hepatitis virus had no increase in miscarriage, low birthweight or perinatal mortality compared with controls who were not infected (Doffler & Voigt, 1966).

Figure 7.3 shows the raised mutation rate caused for a few days by chicken pox as indicated by chromosomal breaks in lymphocytes. It is seen in this diagram that uninfected normal controls had an average 3.8 per cent of lymphocytes with chromosomal breaks. Micronuclei are chromosomal fragments and their number provides another measure of DNA damage. The numbers of micronuclei per 1,000 lymphocytes in 45 healthy people aged 20 to 40 years are shown in Figure 7.4. The random distribution among 45 hypothetical people is shown for comparison, assuming a constant probability of occurrence of micronuclei of 9 per 1,000 lymphocytes. The comparison shows that the variations in micronuclei numbers among the real people were not random, with constant probability, and were not therefore caused by some constant influence.

Eight of the samples from real people had only 2 micronuclei and one sample had 23 micronuclei, results that could not have happened by chance if the 45 real people were, like the hypothetical people, equally at risk. There are major variations in mutation rate between people. A very high mutation rate is characteristic of serious illness and micronuclei per 1,000 lymphocytes can exceed 500. When easier and cheaper methods have been developed for estimating mutation rate it is likely to be used more widely as an indicator of illness. Mutation rate is a useful concept used widely in the literature, but has severe limitations with present methods of measurement. Thus the mutagenicity of the blood fluctuates from day to day and even between evening and morning. It is not generally known how old micronuclei or chromosomal abnormalities in somatic cells are, but it is assumed or implied in many studies that they had their origins in the recent past.

Most of the many causes of mutation in man and animals have been studied using somatic cells, for example leucocytes. Techniques have now been developed for studying the chromosomal abnormalities of human sperm directly; Brandriff et al. (1985) at the University of California investigated the chromosomal integrity of 2,468 sperm cells from 11 donors. Figure 7.5 shows the spread in the apparent mutation rates in the sperm cells of the 11 men from 1.9 to 15.8 per cent, with an average of 7.7 per cent.

Most of the aberrations were chromosomal breaks, but the frequency of aneuploidy ranged from 0.6 to 3.1 per cent. Blood samples were available for 10 of the donors and investigation of lymphocytes showed that 9 out of 10 had a higher frequency of chromosomal aberrations in their sperm cells than in their lymphocytes. The substantial variation in mutation rates between individuals is seen to be as apparent in the mutation0s in germ cells as in blood cells. Viral diseases may not be responsible for the large variations in mutation rate of apparently normal individuals. There are many other causes of mutation. There is nevertheless little doubt that some germ cell mutations are caused by viruses and that it is wise to postpone conception while either parent is suffering from a viral infection and for long enough afterwards for damaged germ cells to be elimi nated.

Not all viral diseases are serious or life-threatening but it is important for couples to understand that benign everyday viral diseases cause temporary increases in mutation rate. Upper respiratory infections are the commonest illnesses reported to family doctors and the common cold has been reported to increase mutation rates (Kurvink et al., 1978). Infections such as tonsilitis have been reported to reduce sperm count and motility temporarily, reflecting a slow-down in DNA synthesis without the sufferers being seriously ill (David, 1982). Secondary infections by bacteria have not been shown to increase mu tation rates.

In times of even mild, benign illness there is an increased consumption of a variety of drugs both off-prescription and prescribed. Watanabe (1979) of the Niigata University School of Medicine studied the embryonic chromosomal anomalies associated with the taking of drugs during the three weeks before and three weeks after the first day of the last menstruation. Data were obtained by karyotyping abortuses obtained by elective abortion. Results are summarized in Figure 7.6 which shows for all drugs, and for all analgesics and antipyretics, a significant increase in chromosomal anomalies associated with drug taking. The number of embryos with chromosomal anomalies (26/117) was too small to show statistical significance for individual drugs separately. A later paper from the same school emphasized that most of the chromosomal anomalies were associated with illness notably acute respiratory illness as well as with the medication (Yamamoto et al., 1982). It can only be said that either or both the illness and medication may have caused the chromosomal anomalies. There are other studies showing that under some circumstances aspirin is mutagenic to sperm (Meisner & Inhom, 1972).

Is it then possible to find out which drugs are mutagenic in what Watanabe calls the perifertilization period? Good information is only available for a very few drugs in spite of an efficient information retrieval service for mutagens and teratogens (EMIC-UK). The literature discourages the use of any drugs by women and by men during the susceptible periods around conception. One review refers to the majority of drugs selected from different pharmacologic classes as spermicidal (Peterson & Freund, 1975). Another study of 10 antibiotics in rats and one in man found that they interfered with the multiplication of spermatogonia or interfered with meiosis I if the spermatocytes survived to this stage. The paper concluded: "This action of antibiotics seems specific to germ cells" (Timmermans, 1974). As spermatogonia are affected a period of 4 months may be needed to eliminate damaged sperm and recover fertility after a course of antibiotics.

THE CASE FOR AVOIDING INFECTION IN ANTICIPATION OF CONCEPTION

Twenty years ago a treatise on prenatal illness concluded a chapter on viral embryopathy by recommending that women should become immune as far as possible to such diseases as rubella, measles, mumps and poliomyelitis before reaching maturity, and that during the preconception period and the first trimester of pregnancy women should where possible avoid exposure to infection (Thalhammer, 1967). In the United Kingdom rubella is still thought to be responsible for 2 to 3 per cent of congenital mental retardation (Ho-Yen & Joss, 1988). It may be desirable to check the titre of rubella antibodies as part of preconception care (Chamberlain & Lumley, 1986).

The long history of listeriosis illustrates the vigilance necessary to avoid foods infected with organisms damaging to reproduction. A Swiss monograph on listeriosis was published in the early 1960s (Seeliger, 1961). Thalhammer (1967) referred to listeriosis as the infection most serious in some communities in its consequences to reproduction. Lang (1955) showed that in rural communities as much as a third of children in the age range 1 to 15 years with brain damage had at some stage, and probably in utero, been exposed to listeriosis. Unpasteurised milk and cheese made from unpasteurised milk are major sources of listeriosis. Inadequate refrigeration can seriously increase the nsk.

Infection with the parasite Toxoplasma gondii is thought to be responsible for 2 to 3 per cent of congenital mental retardation. Under-cooked meat is a major source of toxoplasmosis. Cat faeces and therefore litter trays are another source. The current recommendations for avoiding undercooked meat and unclean cats should be extended from pregnancy to the prepregnancy period. Toxoplasmosis can also cause miscarriage.

Cytomegalovirus (CMV) is reported to be the cause of some 10 per cent of congenital mental retardation in the UK (Hurley, 1983). Infection with CMV is generally asymptomatic in women and there is no specific vaccine or other treatment. Infection can be readily diagnosed from blood samples but tests are unlikely to be done in the absence of symptoms. Infection by CMV is however, like infections with other herpes viruses, a disease of opportunity. Low birth-weight infants growth-retarded in utero have increased susceptibility to many infections and to the herpes viruses in particular (Templeton, 1970). CMV infection can be chronic but probably only in a host with a defective immune status. A diet before conception that reduces the risk of intrauterine growth retardation will also reduce the risk of embryonic and foetal infection and damage to germ cells (Chandra, 1988). he risk of embryonic and foetal infection and damage to germ cells

Sexually transmitted diseases (STDs) are an important group that affects pregnancy outcome and reduces fertility. A consensus report on STDs of the US Institutes of Health concluded that there were 2.5 million cases in the USA each year of nongonococcal urethritis and related chlamydial infections (Wiesner & Pa7rra, 1982). There has been a shift in prevalence from the larger organisms of syphilis and gonorrhoea which are comparatively easy to diagnose, and are amenable to effective antibiotics, to much smaller organisms which are more difficult both to diagnose and to treat, such as chlamydia and the mycoplasmas, papilloma and herpes viruses and HIV viruses. A scholarly book of 652 pages published as recently as 1973 entitled, Obstetric and Pennatal Infections, did not mention chlamydia or papilloma or HIV viruses (Charles & Finland, 1973). The risk of infection from casual sexual contacts has increased but is very unpredictable. There are reports of more than 10 per cent of women in some populations within the developed world being infected with chlamydia and higher percentages with one or other type of STD. The infected women who became pregnant were at greater risk of what was described in a symposium on chlamydial infections as "the constellation of abortion, prematurity, stillbirths and neonatal death" (Thompson et al., 1982). STDs are a major cause of infertility. PopuXation Reports from Johns Hopkins published a review in 1983 of infertility and sexually transmitted disease and concluded:

"For both men and women, the most common preventable cause of infertility is infection... Pelvic inflammatory disease in women, due to sexually transmitted disease (SID) and other infections, probably accounts for more than half of all female infertility in many regions. Although the woman is usually blamed when a couple cannot have children, male factors explain about one-third of all infertility. Low sperm count, often the result of infection, is the most important male factor."

The major percentage of women found to be infertile by the number of episodes of pelvic inflammatory disease (PID) is shown in Figure 7.7 based on a study by Westrom (1980). PID is often difficult to treat as it may become a focus of multiple opportunistic infections. Westrom and Mardh (1983) of the University Hospital, Lund, concluded a review in the British Medical Bulletin:

"...Now and for many years to come we will have to harvest the seed of the STD and salpingitic epidemic of the 1960s and 1970s in terms of the many women deprived of the possibility of motherhood because of postinfection tubal damage".

Throughout much of the world the epidemic has continued since the 1970s. The 1981 consensus report of the US National Institutes of Health concluded that one of the commonest STDs to prejudice male fertility is chlamydia (Wiesner & Parra, 1982):

"Chlamydia trachomatis is the major cause of nongonococcal urethritis (NGU) in men, which is twice as common as gonorrhoea. Chlamydia causes more than one-half of the 500,000 cases of epididymitis occurring each year. This painful complication of NGU is potentially sterilizing."

In the United Kingdom chlamydia is reported to be the commonest sexually transmitted pathogen, causing 35 to 40 per cent of cases of so-called "nonspecific" infection (Alexander, 1988). Fifteen to 17 per cent of chlamydia is reported in asymptomatic patients attending clinics.

Population Reports (1983) suggests that as many as 20 to 25 per cent of nongonococcal urethritis cases in the USA are caused by mycoplasmas. Mycoplasmas, like the chlamydial organisms, can ride on spermatozoa and reduce motility (Chang et al., 1984; Wolner-Hanssen & M?trdh, 1984). The evidence that mycoplasma infection reduces male fertility is more convincing than its effect on the female (Toth et al., 1980). The mutagenicity of mycoplasmas was, however, reported by Kundsin et al. in 1971 and has been confirmed in many subsequent studies. The full human consequences of mycoplasma infec tion remain to be explored. These organisms adhere to sperm, enter the uterine cavity and the fallopian tubes causing obstruction.

Genital herpes is an STD associated with miscarriage, low birthweight, malformations and foetal infection (Hurley, 1983) and is mutagenic as shown in Figure 7.8 from Ghosh and Ghosh (1983) in cell culture experiments using blood lymphocytes from infected patients and controls. The frequency of sis ter-chromatid exchange used in this study is an indicator of chromosomal damage. Genital herpes is generally regarded as a localized infection confined to the genitalia but Ghosh and Ghosh showed that genital herpes multiplies in the genitalia and is released into the blood and that the amount of chromo somal damage is linearly related to the amount of antibody in the case of both types of herpes. The resulting viraemia affecting all body systems may be very slight in a patient with a healthy immune system. Herpes is, however, a fatal disease among ill-fed peoples in the developing world.

The papilloma viruses, named after the warts or papillomas that they cause, are another family of STDs, with a reported incidence in England & Wales higher than for herpes virus. The prevalence of papilloma virus in the USA and Europe has been increasing (Blank, 1986). Papilloma viruses like herpes viruses are more serious in immunosuppressed or ill-fed people. Papilloma viruses are also mutagenic and cause chromosomal aberrations in the cells that they infect (Evered & Clark, 1986).

The increased prevalence of some STDs is partly a consequence of the increased mobility of people. The number of persons travelling between cities and between countries has increased and is forecast to continue to increase. No doubt the prevalence of syphilis and gonorrhoea would have increased if it were not for the excellent medical services, armed with antibiotics for treatment, available in the United Kingdom and elsewhere. Syphilis and gonorrhoea are not reported to be mutagenic. The viral diseases are a more difficult and increasingly serious problem. Papilloma and herpes viruses and indeed chlamydia are already the subject of a substantial literature suggesting that they cause cancer and in particular cervical cancer responsible for about 2,000 deaths of women every year in the UK. Unlike chemicals or radiation viruses can produce mutations at specific locations in somatic and germ cells which are peculiar to the particular virus types. Many of the consequences of STD viral infection have yet to be discovered. The current publicity about HIV infections and AIDS has shown to the public the great difficulty in treating virus diseases. A leading article about HIV in the British Medical Journal concluded (9 August 1986):

"True, the virus has been isolated; but so have the viruses of hepatitis, influenza, rabies, and other fatal diseases, and we still have no treatments. All the evidence suggests that the development of a vaccine will prove immensely difficult."