Introduction

Rubella virus belongs to the rubivirus genus of the family Togaviridae, for which humans are apparently the only host. Rubella is an enveloped single-stranded RNA virus which is relatively fragile, multiplies in and is transmitted from the respiratory tract of infected individuals. The virus gains access to the bloodstream resulting in widespread dissemination throughout the body. In pregnant women, rubella can infect the placenta leading to fetal infection with varying degrees of fetal damage. Attention was first drawn to the association between rubella and fetal damage when Gregg, an Australian ophthalmologist noted an epidemic of congenital cataracts following a large outbreak of rubella (Gregg, 1941). Similar reports followed from Sweden, the US and the UK and the role of rubella in congenital cataracts was confirmed. The coincidence of heart disease and deafness was also noted (Plotkin & Mortimer, 1994). Rubella infection is often asymptomatic or causes only mild disease, and the importance is confined to infection during pregnancy and its possible effects on the fetus, referred to as the congenital rubella syndrome (CRS).

Rubella infection is readily prevented by a highly effective and safe live attenuated vaccine which when given to all infants and susceptible adults, as is the case in much of the developed world, has virtually eliminated cases of the congenital rubella syndrome. However, rubella can still be prevalent in immigrant populations from countries where vaccination is not common (Tookey & Peckham, 1999).

Clinical features of rubella

In children rubella infection is usually either asymptomatic or with mild constitutional symptoms accompanied by an evanescent rash, which is often missed. In adults, infection is generally accompanied by an illness although this is likely to be mild.

Introduction

This chapter discusses aspects of five reproductive tract infections (RTIs) on maternal and infant health. The five RTIs considered are gonorrhoea, chlamydial infection, genital mycoplasma infection, trichomoniasis and bacterial vaginosis. These infections are very common in resource-constrained settings and are the cause of significant morbidity for women and their children. Syphilis and HIV are discussed in other chapters.

Neisseria gonorrhoeae infection in pregnancy

Epidemiology

Globally, the prevalence of gonococcal cervical infections in pregnant women varies widely geographically (Table 14.1). In Western Europe and Canada, the prevalence of gonorrhoea in pregnant women is very low. In the USA prevalence in pregnant women varies widely. In sub-Saharan Africa, Asia, Latin America and the Caribbean, gonococcal infection prevalence rates in pregnant women and family planning clinic attenders vary widely, but are also much higher than in industrialized areas. Overall, the burden of gonococcal infection in developing countries is increasing due to its rising prevalence and to the increasing cost of treatment, after the widespread emergence of resistance to inexpensive antibiotic therapy (Ison et al., 1998).

Risk factors for gonococcal infection appear to be the same in pregnant as in non-pregnant women. Studies in North America have shown that individuals with the highest rate of detected gonorrhoea live in urban areas, are young, non-white, unmarried, of low socio-economic status and with a prior history of gonorrhoea (Barnes & Holmes, 1984).

Introduction

More than 33 million people were living with HIV by the end of 1998. According to UNAIDS estimates, 22.5 million of these were in Africa (67%), and 6.7 million in South and Southeast Asia (20%). Close to six million new infections are occurring each year, with 10% of these in children, the majority as a result of mother-to-child transmission (MTCT) (UNAIDS, 1998). An estimated one and a half to two million HIV-infected women will become pregnant each year, with 1600 children each day infected by mother-to-child transmission.

In Europe, the increase in heterosexually acquired HIV infection in women of childbearing age has been paralleled by increasing numbers of infected children. Antenatal HIV prevalence in Europe is generally below 5 per 1000 deliveries, although variable: higher in selected groups and inner cities. In a number of countries in Africa south-of-the-Sahara, 10–25% of pregnant women are infected, with rates of over 40% reported in parts of Southern Africa (US Bureau of the Census, 1999; Stanecki & Way, 1999). Southeast Asia has seen a rapid rise in infection rates in some areas.

HIV infected children most commonly present early in life with non-specific clinical manifestations. About one-quarter of infected children will develop AIDS in the first year of life, but the progression of disease in the remainder is much slower. In developed countries about 75% of infected children are alive by age 5 years, and in developing countries about 40% (French Pediatric HIV Infection Study Group and European Collaborative Study, 1997). HIV/AIDS has increased infant and child mortality dramatically in the most affected African countries, and is expected to lead to a doubling of under-5 mortality by 2010 in southern African countries.

The virus

Cytomegalovirus (CMV) is an enveloped DNA virus and a member of the herpes family which also includes herpes simplex, Epstein–Barr and varicella-zoster viruses. Like other herpes viruses, once primary infection has occurred the virus establishes itself in the host in a latent form, possibly in peripheral blood mononuclear cells, and may periodically reactivate (Jafari et al., 1995). During active infection CMV is found in epithelial cells (Griffiths & Grundy, 1998). Infection is controlled by cellular and humoral immune responses, with the cellular responses being the most important and much of the tissue damage associated with CMV infection is probably due to the immune mediated inflammatory reaction to infected cells expressing CMV antigen (Griffiths & Grundy, 1998). CMV is probably transmitted through infected secretions coming into contact with mucous membranes, but not through intact skin. Droplet infection seems to play a minor role. The virus is unstable outside the body and is vulnerable to ordinary soaps, detergents, commonly used disinfectants and heat. Normal hygienic procedures should thus substantially reduce, or eliminate, the risk of transmission of infection.

Both primary and recurrent (with the same or a different strain) infections are associated with viral shredding in body fluids, including urine, saliva, semen, cervical secretions and breast milk. In healthy individuals symptoms of CMV infection are usually mild or not apparent and rarely cause serious illness. However, infection can be life threatening in immunocompromised individuals and in very premature infants, and when acquired in pregnancy it can result in fetal damage (Fig. 7.1).

Introduction

The issue of neonatal sepsis remains a vexing problem, despite great advances in neonatal care, as it is a potentially fatal condition that is difficult to diagnose. Clinical signs are vague and non-specific and there is no easily available, reliable marker of infection. If left untreated, a baby with sepsis can deteriorate rapidly and may die. As a consequence, many neonates are evaluated and treated for ‘suspected sepsis’ unnecessarily, with associated costs in terms of drugs, prolonged hospitalisation and parental anxiety. It is estimated that between 11 and 23 neonates are treated for each documented case of sepsis (Gerdes, 1991). In a recent study, less than 20% of neonates evaluated for suspected sepsis were subsequently confirmed to have definite or probable sepsis (Magudumana et al., 1999). Neonatal sepsis classically occurs in two distinct time periods – early (< 7 days) or late (> 7 days). The most typical example of this infection is group B streptococcus, with early onset infection affecting 0.1 to 0.4% of neonates and a mortality rate of 15 to 45%. Late onset, or nosocomial, infection occurs in as many as 25% of hospitalised neonates and mortality rates are between 10 and 20% (Harris, 1993). It should be noted, however, that the incidence and mortality rates of neonatal sepsis vary greatly between different geographical areas. Neonatal sepsis will be discussed in this chapter, with special emphasis on the more recent advances that have taken place in the diagnosis and management of these neonates.

Risk factors

General

Neonates presenting with infection during the first week of life were almost certainly exposed to microorganisms colonizing the maternal genital tract during the intrapartum period (Harris, 1993).

Introduction

Hepatitis is a general term for inflammation of the liver due to a variety of causes, of which viruses are the most common, but which can also include toxic and auto-immune disorders. The consequences of liver disease in pregnancy, including maternal and fetal outcome, are beyond the scope of this chapter, which focuses on vertical transmission. Acute hepatitis in the mother must be distinguished from other types of liver disease, either unique to pregnancy, such as cholestasis of pregnancy, acute fatty liver of pregnancy and preeclampsia / HELLP syndrome, or pre-existing liver disease, such as cholelithiasis. Although a number of viruses, including herpes simplex and cytomegalovirus, can cause hepatitis, viral hepatitis refers to infections caused by the hepatitis viruses.

Six distinct hepatitis viruses are known: A, B, C, D, E and G, which are not easily distinguished on clinical grounds. Hepatitis A and E are transmitted by the faecal-oral route, and are not commonly transmitted vertically. However, they can cause either asymptomatic infection or fulminating acute hepatitis, notably for HEV in pregnant women. HBV, HCV, HDV and HGV are bloodborne agents, which can lead to chronic carriage, and subsequently to mother-to-child transmission. The clinical significance of HGV remains undetermined, and HDV is dependent upon co-infection with HBV for replication. Hence, HBV and HCV are the most important. They have similar epidemiological and clinical features, and in both infections, asymptomatic carrier mothers can be identified only if serologic testing is performed. Yet there are also important differences. HBV has been known for decades, has a high risk of mother-to-child transmission, with potentially serious long-term consequences for the child, but which can be effectively prevented with immune prophylaxis.

Introduction

Historically, varicella (chicken-pox) infection in pregnancy has received less attention than other causes of congenital infection (such as the ‘STORCH’ group, syphilis, toxoplasmosis, rubella, cytomegalovirus and herpes virus). Recent work has highlighted the importance of varicella as a cause of both congenital and perinatal infections. Recognition of the ultrasound features of congenital varicella infection has contributed to a rational approach to maternal varicella infections during pregnancy.

Prevalence

Varicella is a common childhood infection caused by the varicella-zoster virus (VZV). The historical events spanning the first half of the twentieth century which led to the recognition that varicella and zoster are caused by the same virus, have recently been summarized by Weller (1996). Varicella is relatively uncommon in adults but the proportion of infections reported in adults is increasing, and is particularly high in tropical countries.

Varicella is highly infectious, with attack rates of up to 90% in household settings. Respiratory secretions and the skin lesions are infective, and the infective period is from 2 days before appearance of the skin lesions until the lesions have crusted. The incubation period is 10 to 21 days (mean 15 days). The rash may be preceded by a 1 to 2 day prodromal illness with fever, headache, malaise and anorexia. The fever lasts 1 to 3 days if present. The severity of these symptoms increases with age. The rash affects the trunk, scalp, face and extremities, and progresses over the period of a week from macules to papules, vesicles, pustules then crusted lesions.

Introduction

Congenital syphilis is a serious and preventable disease, which remains an important cause of infant morbidity and mortality (Sciarra, 1997; Finelli et al., 1998). Treponema pallidum can be transmitted from an infected woman to her fetus, particularly when the mother presents with syphilis in the primary, secondary or early latent stage (Fiumara, 1952). In adults the primary lesion appears at the initial site of the infection about 3 weeks after exposure, followed by a more generalized illness involving skin rashes and condylomatalata after 6–12 weeks (secondary syphilis). If untreated, this stage is self-limited and the patient usually progresses to a latent stage of infection during which the only evidence of syphilis is positive serology. During the early latent phase (within 2 years of onset) organisms can be seeded intermittently into the blood stream.

Transmission from mother to infant can occur after at any stage of pregnancy, so that early antenatal serological screening with treatment of infected women prevents most cases of congenital syphilis (Sanchez et al., 1996). Detection in late pregnancy is less effective, but may prevent some of the sequelae. Untreated syphilis in pregnancy may result in significant perinatal mortality and morbidity, the risk depending on the stage of infection in the mother and levels of spirochetes in the blood stream (Wendel, 1988; Larkin et al., 1998). During the first 2 years of untreated latent maternal infection an estimated 20% of infants will die in utero or in the neonatal period, 20% will be premature but otherwise normal, 40% will be infected and damaged and 20% will be uninfected (McDermott et al., 1993).

Introduction

Pregnancy is a vulnerable period for the acquisition of infections and infectious diseases. Not only can the pregnant woman herself become infected, but fetal and/or neonatal transmission may also occur. Although pregnancy does not usually affect the incidence and severity of infections, some physiological adaptations of pregnancy can result in increased risk for some infections particularly urinary tract infections, pneumonia and chorioamnionitis. In addition to maternal sequelae, the developing fetus is often placed at risk secondary to hyperpyrexia, hypoxia, preterm labour and congenital infection. The number of maternal infections known to be associated with adverse pregnancy outcomes continues to increase. Adverse pregnancy outcomes can be a direct consequence of fetal or neonatal infection or an indirect effect secondary to vaginal, cervical or intrauterine infections. Specific fetal risks are highly dependent on the causal organism, potential for transplacental passage, timing of exposure and maternal/ fetal immune status. Adverse outcomes associated with maternal infection during pregnancy are varied and include infertility, ectopic pregnancy, miscarriage, congenital anomalies, stillbirth, intrauterine growth retardation, preterm delivery, neonatal death, and long-term disability of the infant.

Maternal infection and pregnancy

Infections are common during pregnancy, but the risks associated with infections vary by pathogen and disease site (Alexander, 1984). Infections such as acute cystitis, upper respiratory viral infections and trichomoniasis are generally of concern for maternal health but pose less risk to the fetus. In contrast, infections such as cytomegalovirus (CMV), genital herpes simplex virus (HSV), parvovirus, and rubella can lead to significant fetal morbidity/mortality but have little or no maternal sequelae. Similarly, relatively innocuous constituents of the genital and rectal flora, such as group B streptococcus (Streptococcus agalactica) and Escherichia coli, may represent benign maternal colonization.

Papillomavirus infections as a perinatal problem

Human papillomaviruses (HPVs) are DNA viruses; more than 100 HPV types have been identified to date. HPV types are categorized into low- and high risk, depending on the sort of lesions they induce, such as benign hyperplastic lesions, cancer precursors or invasive cancers. Different HPV types are capable of infecting skin and a variety of mucous membranes at different anatomical sites, including the genital tract, gastrointestinal and respiratory tracts (Syrjänen & Syrjänen, 2000). In addition, HPV lesions have been found in the urinary tract and in the eye (Chan et al., 1997; McDonnell et al., 1987).

There is a strong causal relationship between HPV and cervical cancer (zur Hausen, 1994; Schiffman et al., 1993; Millikan, 1994; Bosch et al., 1995). Indeed, certain high-risk types (HPV 16 and 18) are the single most important risk factors of cervical cancer (IARC, 1995), and are likely to also be implicated in other human malignancies. It has been estimated that up to. 10–15% of all human malignancies might be linked with HPV infections (Syrjänen & Syrjänen, 2000). In the present chapter, issues relating to perinatal acquisition of HPV infections are discussed. Other manifestations (e.g. laryngeal papillomas) of HPV are discussed only as far as pertinent to their transmission by the vertical route.

Prevalence and Incidence

Genital HPV infection is considered to be a primarily sexually transmitted disease (STD) and most studies have concentrated on HPV infections of the genital tract. However, despite the ubiquitousness of HPV infections with an estimated life-time risk of genital infection of 80% (Syrjänen et al., 1990), few people have clinically detectable genital HPV lesions at any point of time.

Introduction

Herpes simplex type 1 (HSV-1) and 2 (HSV-2) infections are common in pregnant women; the symptoms – if any – are generally mild. However, HSV infection during pregnancy can result in transmission of the virus to the neonate, sometimes with serious disease and severe sequelae in the child (Nahmias et al., 1983; Koskiniemi et al., 1989; Malm et al., 1991; Azazi et al., 1990; Whitley & Arvin, 1995). Prevention is difficult, as the majority of HSV infections during pregnancy are atypical or silent. Furthermore, in the neonate vague symptoms are often not recognizable as herpes simplex disease, and early treatment of an infected child is therefore usually not an option.

Transmission of herpes simplex virus infection to the neonate is rare, which makes identification of risk factors for transmission and evaluation of preventive strategies difficult. Although results from large multicentre studies and the use of improved virological diagnostic tools have contributed to knowledge, formulation of evidence-based recommendations for prevention and management is still not possible. Management of HSV infection in pregnant women and children may also be influenced by non-medical factors, such as anxiety.

The prevalence of herpes infection – genital and oral – varies by populations of pregnant women and so does the risk of neonatal herpes. Preventive strategies should be guided by the incidence of neonatal infections. For an estimate of the real rate of neonatal herpes, surveillance studies based on active search for neonatal infections have to be undertaken in collaboration between neonatologists and virological laboratories.

Introduction

Infection, particularly puerperal infection, has been a persistent threat to successful reproduction, and generations of women have lost their lives during and after childbirth as a result of infectious disease. Major epidemics of puerperal sepsis, such as that described by Peu in Paris in 1664, and that which occurred in Lombardy in 1772, left few if any survivors (Graham, 1950), and the vectors of infection were the doctors more often than not. The work of Holmes in 1843 and of Semmelweiss in 1861 led to the recognition of infection as the cause of ‘childbed fever’, and eventually resulted in a reduction in the role of the obstetrician as the bearer of the causative microorganisms. For this and other reasons, sepsis is no longer an epidemic killer of puerperal women.

Survival in a world surrounded by hostile and potentially harmful organisms depends upon the development of defence mechanisms. Clearly, the first line of defence will be an intact skin, and the employment of physical and chemical measures to enhance its impenetrability.

However, existence also requires that there be interaction with the surrounding environment. The assimilation of nutrients and oxygen dictates that the external defence be breached and, inevitably, microorganisms will accompany whatever is absorbed. When microorganisms have entered the body, defence depends upon the development of an immune response.

Introduction

Toxoplasma gondii occurs throughout the world and is one of the most common parasitic infections of humans. Infection is acquired by ingestion of viable tissue cysts in undercooked meat, or of oocysts excreted by cats and contaminating soil or water (Remington et al., 1995). Acquisition of toxoplasma infection for the first time (primary infection) is usually asymptomatic although a significant minority of people suffer fever, malaise and lymphadenopathy (Ho-Yen, 1992a). As the primary infection resolves, the parasite forms latent cysts throughout the body. In approximately 1% or less of people infected with T. gondii, latent cysts in the retina and choroid can reactivate, often years after infection, and give rise to inflammatory lesions, which may affect vision (Gilbert & Stanford, 2000). Toxoplasma infection is a major cause of morbidity and mortality in immunodeficient patients (Ho-Yen, 1992b).

When primary infection occurs during pregnancy, T.gondi may be transmitted from the mother to the fetus. Fetal infection can result in inflammatory lesions in the brain, retina and choroid that may lead to permanent neurological damage and visual impairment. Rarely, disseminated fetal infection causes fetal or postnatal death. Approximately 1–10 per 10,000 babies are born with congenital toxoplasmosis (Ancelle et al., 1996; Conyn-van-Spaedonck, 1991; Guerina et al., 1994; Lebech et al., 1999).

How best to prevent symptoms and disability due to congenital toxoplasmosis is a question that has caused controversy among clinicians for the last three decades. At the core of the debate is uncertainty about the effectiveness of prenatal treatment on the risk of congenital toxoplasmosis, and of prenatal and postnatal treatment on the risk of clinical signs and symptoms in the long term.

Healthy pregnant women are not usually more susceptible to infections than non-pregnant women, but when infections occur during pregnancy there is often considerable concern about the possible adverse effects on the fetus or newborn. Perinatal infections remain a major cause of morbidity and mortality in infants in both the developed and developing world, and the range of infections known to be associated with perinatal infections continues to increase. Diagnosis has improved with new diagnostic techniques, including advanced serological techniques and ultrasonography.

Doctors in obstetrics and paediatrics and their midwifery colleagues need to be aware of recent advances in knowledge with regard to these conditions, which can translate to preventive measures and which have implications for decisions regarding antenatal screening packages. Several exhaustive reference books exist; and this book is not intended to replace these. We hope that it will provide a concise up-to-date review of the field which will provide easily accessible information, with an explanation of the underlying mechanisms and approaches to prevention, for medical practitioners of all disciplines. The authors are all experts in their fields, drawn from both developed and developing countries, which we hope will add to the relevance of this book for all settings.

Introduction

Infections in pregnancy that can be transmitted from mother to child are of particular concern since congenital or perinatal infections may be associated with adverse sequelae. Maternal infections that have the potential of infecting the fetus or newborn infant are listed in Table 1.1 and include viral, bacterial and protozoal infections. The consequences and management of individual infections are discussed in detail elsewhere in this book. The purpose of the present chapter is to present an overview of the salient features and issues that arise in relation to the detection and management of infections in pregnancy, largely from a population perspective. This epidemiological knowledge is needed to establish a causal relationship between an infection and the outcome, to inform decisions about screening in pregnancy and also to ensure the most appropriate management of a woman with a specific diagnosed infection in pregnancy.

All the infections listed in Table 1.1 can cause fetal or perinatal infection, sometimes associated with an adverse outcome such as fetal loss, stillbirth, prematurity, fetal damage, or acute neonatal infection. For some congenital infections there may be no evidence of symptoms or signs of infection in the neonatal period and it may be weeks, months or even years before damage first becomes apparent (Table 1.2).

Mode of acquisition of infection

The route by which the fetus or newborn acquires the infection has important implications for the management of the infection in pregnancy, or in the neonatal period, and for the development of appropriate intervention programmes to prevent mother-to-child transmission. Infections of the newborn maybe acquired in utero (congenital infection), around the time of delivery (intrapartum infection) or in the neonatal period (postpartum infection) (Table 1.3).

Introduction

Infection is a major cause of perinatal morbidity and mortality (Christensen, 1982; Ohlsson et al., 1987). The aetiology of neonatal septicemia varies with geographical location and changes over time (Nyhan & Fousek, 1958; Ohlsson & Serenius, 1981; Ohlsson et al., 1986). From the 1960s onwards, Group B beta-haemolytic streptococcus (GBS) has been one of the most common causes of neonatal infectious morbidity and mortality in the USA (Eickhoffet al., 1964; Franciosi et al., 1973; McCracken, 1973), Canada (Allardice et al., 1982), the UK (Reid, 1975; Lloyd & Reid, 1976), Europe (Cayeux, 1972, Bergqvist, 1974; Bergqvist et al., 1978; Schroder & Paust, 1979; Speer et al., 1985; Vesikari et al., 1989) and Australia (Fliegner & Garland, 1990). GBS causes significant maternal perinatal morbidity (Institute of Medicine, 1985), bacteriuria in pregnancy (Hastings et al., 1986) as well as urinary tract (Munoz et al., 1992) and other infections in the adult non-pregnant population (Opal et al., 1988; Schwartz et al., 1991).

Historical background

Rebecca Lancefield described in 1933 a serological method for differentiating the haemolytic streptococci into a number of groups (Lancefield, 1933). At that time most severe streptococcal infections in the puerperium were caused by streptococci belonging to Group A (Charles & Larsen, 1986). In 1935 GBS was reported as a cause of mild puerperal infection (Lancefield & Hare, 1935), followed by a report of three cases of fatal GBS puerperal infection (Fry, 1938). GBS was subsequently confirmed as an important pathogen in the perinatal period (Nyhan & Fousek, 1958; Eickhoffet al., 1964; Franciosi et al., 1973; Hood et al., 1961).

The organism

The GBS, or Streptococcus agalactiae, is a Gram-positive diplococcus. The majority of strains (99%) are beta-haemolytic.