Infections of mothers and their babies (both in utero and ex utero) are a major global health challenge. Bacterial infections arise from many sources, both natural and iatrogenic, and affect mothers and babies in a variety of ways. Viruses are often more virulent in pregnancy, and can produce different effects in the pregnant, as opposed to the nonpregnant, woman. Although not intended to be a comprehensive collection, the articles presented in this special themed issue of BJOG illustrate the consequences of important microbial infections during pregnancy, review potential causative mechanisms and give examples of prevention and treatment strategies, available both now and potentially in the future.
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Preterm birth and the immune response
A major consequence of bacterial invasion of the amniotic cavity is the induction of premature myometrial contractions followed by preterm delivery. Evidence is accumulating that some of the inflammatory mediators exert direct neurotoxic effects on the developing fetal brain and also increase susceptibility to damage by other noxious agents. Future efforts to reduce the rate of preterm birth depend upon gaining an improved understanding of the causative mechanism(s), determining differences in individual susceptibility, and identifying specific early-stage biomarkers that will allow the development of novel and timely intervention strategies. The pioneering studies on nonhuman primates reviewed by Adams Waldorf et al. (page 136) provide a comprehensive background to the sequence of events, progressing from intrauterine infection to proinflammatory cytokine activation, prostaglandin production, premature contractions, cervical changes and premature delivery. Furthermore, they clearly demonstrate that once an infection is established and the proinflammatory cytokine pathway is triggered, antibiotic administration alone is unable to prevent infection-induced preterm labour. However, in their monkey model, a combination of antibiotic plus immune modulator (dexamethasone, indomethacin or a Toll-like receptor 4 antagonist) successfully prevented premature myometrial contractions despite the presence of infection. The potential of this approach for reversing human preterm labour awaits further advances in our understanding of infection-related mechanisms as well as a full examination of safety issues.
The immune responses to infectious agents during pregnancy, compared with the nonpregnant state, are reviewed by Witkin et al. (page 145). It is becoming increasingly apparent that women have evolved a unique and diverse set of immune resistance and tolerance mechanisms during gestation to modulate the immune response to infectious stimuli, which allows for effective maintenance of immunological processes while preventing damage to developing fetal organs or the triggering of preterm delivery. Genc and Onderdonk (page 154) bring us up to date on bacteria that are normally present in the vagina and how variations (polymorphisms) in a woman’s immune response genes can alter the composition of this flora and influence the likelihood of bacterial migration to the amniotic cavity and induction of premature labour. Taylor-Robinson and Lamont (page 164) review the effects of Mycoplasma species during pregnancy; their pathogenicity remains controversial. Studies on monkeys by Adams Waldorf et al. (page 136) and on pregnant women in premature labour by Holst et al. (page 240), have identified potential biomarkers in amniotic fluid and in cervical secretions for the early detection of intra-amniotic infection. In humans, elevated cervical concentrations of monocyte chemotactic protein-1 and interleukin-17 were the best indicators of early microbial intra-amniotic invasion. These studies could lead to sensitive clinical assays to successfully predict, and eventually treat and prevent, infection-related preterm birth.
It has remained unclear whether bacteria associated with periodontal disease actually induce preterm birth or if it is merely the same genetic factors that foster bacterial growth in the lower genital tract that also allow the proliferation of oral bacteria. Relevant new information regarding a more direct association between periodontal infection and preterm birth is presented in this issue by Jeffcoat et al. (page 250). Among pregnant women with periodontal disease, those who were successfully treated had a significantly lower rate of preterm delivery than women whose periodontal disease persisted after treatment.
Although still controversial, there is indirect evidence that in preterm birth associated with suspected chorioamnionitis, antenatal steroid administration is at least safe (for the mother) if not overly effective (for the neonate). A systematic review and meta-analysis by Been et al. (page 113) of eight observational studies evaluated the efficacy and safety of antenatal steroids in clinical and in histological chorioamnionitis. It suggests that antenatal steroid use is safe and reduces adverse neonatal outcome, although the authors recommend further randomised controlled trials to settle the issue.
Taking forward conventional ideas and practices
Sometimes common bacterial infections that usually have relatively minor consequences can produce disastrous outcomes. Śledzińska et al. on page 266 describes a fatal case of overwhelming sepsis from Escherichia coli urinary tract infection. Although we do not usually accept case reports, the accompanying commentary by Nowicki (page 109) on the pathogenesis of urinary tract infection in pregnancy was novel, and challenges conventional wisdom by focusing on the relative roles of urinary obstruction, immune adaptation and microbial virulence. In their paper on wound infection after caesarean section, Lamont et al. (page 193) contest another convention—that of antibiotic administration after umbilical cord clamping and discuss the evidence supporting preoperative antibiotic use.
Daniels et al. (page 257) report on the test characteristics of a polymerase chain reaction-based intrapartum kit for the detection of maternal group B streptococcal (GBS) colonisation. Although culture of a rectovaginal sample for GBS between 35 and 37 weeks of gestation is the standard for routine screening, there is a small but significant discrepancy between maternal GBS colonisation at 35–37 weeks of gestation and during labour, which has prompted a search for a rapid bedside test. Daniels et al. report on such a tool; they found it to be a more accurate predictor of maternal and neonatal GBS colonisation compared with optical immunoassay or risk-factor-based screening, while also being acceptable to women. Their paper makes a strong case for the revision of the criteria for intrapartum antibiotic prophylaxis for GBS, and for GBS testing by polymerase chain reaction, in the UK.
Recent influenza pandemics have sensitised the medical community to the potential consequences of viral infections in pregnant women. In this issue, Knight et al. (page 232) detail the consequences of AH1N1v influenza on pregnant cohorts in the UK and Australia. Viral infections, especially in nonimmune pregnant women, pose a serious threat to maternal and neonatal wellbeing. Current investigations and unmet needs in the prevention of neonatal herpes virus infection are comprehensively reviewed by Gardella and Brown (page 187). This infection, the incidence of which has not declined in recent decades, remains a major burden worldwide and there remains a challenge to lessen its transmission and consequences during gestation. Human parvovirus B19 infection is also prevalent worldwide and commonly transmitted among school-age children. The consequences for nonimmune pregnant women and their fetuses who contract this infection through contact with infected children are reviewed by Lamont et al. (page 175).
Infections in resource-poor settings
Malaria, HIV/AIDS and tuberculosis cause approximately five million deaths every year. Most of the burden of these diseases occurs in the poorest countries in the world and causes mortality primarily in pregnant women and their children. Moodley et al. (page 219) use data from South African confidential enquiries into maternal deaths to illustrate the higher maternal mortality experienced by HIV-infected women compared with those who are not infected. Identifying HIV-infected women must be made a priority but, sadly, the uptake of HIV testing in pregnancy remains low. The authors recommend strategies that have been known for years—preventing unwanted pregnancies, preventing HIV transmission and managing complications effectively. This only serves to call attention to one of the main underlying reasons why women continue to die during pregnancy in poor countries—we know what to do, but we do not seem to be able to implement it effectively. The review by Mepham et al. (page 202) reminds us of the inequities that exist between resource-rich and resource-poor settings for treatment and management of mother-to-child transmission of HIV. The avoidance of breastfeeding and elective caesarean section are two fundamental means of preventing mother-to-child transmission in richer countries. Neither strategy sits comfortably in resource-poor environments. Not being breastfed will expose infants to other life-threatening conditions such as diarrhoea and malnutrition, so the idea of continuing prophylaxis of the mother or infant beyond the usual postpartum period for up to a year after delivery provides a promising alternative. Caesarean sections are not always a low-risk option for pregnant women in developing countries, and not enough is known about whether at least some women can deliver vaginally while limiting the risk of mother-to-child transmission. Although we know that prevention of mother-to-child transmission can be reduced considerably by the use of antiretroviral therapy in pregnancy, we still do not know how to effectively reduce the risk of maternal mortality or morbidity in pregnant women with HIV.
The recent success in the detection and treatment of tuberculosis worldwide is undermined by HIV infection. Co-infection with HIV compounds the management of tuberculosis and remains a major problem. Mnyani and McIntyre (page 226) review the recommended management of tuberculosis in pregnancy and also highlight conflicting information on the effect that tuberculosis has on pregnancy outcomes. In a systematic review of 60 trials, McGready et al. (page 123) examined the efficacy of antimalarials used for treatment and chemoprophylaxis of malaria in pregnancy. Their paper is particularly important because of the constant emergence of parasite strains resistant to all classes of antimalarials and the lack of good evidence to inform the treatment and prevention of malaria in pregnancy. The authors argue for the need for better treatments and for abandoning ineffective drugs.
It seems that there is much to be done to understand how best to prevent the mortality and severe morbidity caused by infections in pregnancy, especially in the developing world. New discoveries for old problems are always needed, and we should remember that the historical bane of obstetricians and midwives—puerperal sepsis—continues to cause up to 12% of maternal deaths worldwide and remains to be eradicated. The latest confidential enquiry into maternal mortality in the UK (triennium 2006–08) has reported that genital tract sepsis is once again the leading cause of mortality, with 29 deaths (mainly as the result of community-acquired β-haemolytic streptococcus Lancefield Group A [Streptococcus pyogenes]). Clearly, much still needs to be done to understand causative mechanisms and to implement measures to better prevent mortality and morbidity from infections in pregnancy. This remains a major concern for both the developed and developing world. It is our hope that this theme issue will inspire and motivate increased efforts in this area.