Infectious Diseases and Prematurity

Data derived from molecular microbiological investigations of the human vagina have led to the discovery of resident bacterial communities that exhibit marked di ﬀ erences in terms of species composition. All undergo dynamic changes that are likely due to intrinsic host and behavioral factors. Similar types of bacteria have been found in both amniotic ﬂuid and the vagina, suggesting a potential route of colonization. Given that not all of the species involved in intrauterine infections are readily cultivated, it is important that culture-independent methods of analysis must be used to understand the etiology of these infections. Further research is needed to establish whether an ascending pathway from the vagina to the amniotic cavity enables the development of intrauterine infections. Objective . To assess the e ﬀ ect of universal screening and administration of intrapartum antibiotic prophylaxis to prevent early-onset neonatal GBS sepsis at a private tertiary care hospital since issuance of the 2002 CDC guidelines for preventing perinatal GBS disease. Methods . Retrospective analysis of women delivering between January 1, 2003 and December 31, 2004 at a private tertiary care hospital in Houston, Texas. The percentage of women screened, GBS positive women receiving intrapartum antibiotic prophylaxis, and infants developing early-onset GBS sepsis were determined. Results . 2,108 women delivered 2,135 infants with 1,874 (89%) screened for GBS. Of those screened, 1,322 (71%) tested negative and 552 (29%) tested positive for GBS. In this analysis of 2,135 infants, 3 (0.94 cases/1,000 live births) were diagnosed with invasive GBS sepsis. Conclusion . High rates of screening of pregnant women for GBS colonization and use of intrapartum antibiotic prophylaxis for GBS carriers can be achieved in a private tertiary care hospital setting. “Synopsis: High screening rates for group B streptococcus in a private tertiary care hospital reduce the incidence of maternal and early onset neonatal GBS infection.” Asymptomatic term neonates born to mothers who are Group B Streptococcus (GBS) unknown or GBS positive but “inadequately” treated prior to delivery do not require invasive laboratory evaluation. We conducted a retrospective cohort study of mother/baby dyads born from January 1, 2005 until September 30, 2007 at the Medical College of Georgia. Their current protocol is to obtain a Complete Blood Count with Di ﬀ erential (CBC with D), Blood Culture (BC), and C-reactive protein (CRP) after birth. Mother/baby dyads ( n = 242) that met inclusion criteria were reviewed. Of these 242 babies 25 (10%) were started on antibiotics after the initial lab values were known. None of the blood cultures were positive and the CRP’s were normal. The 2002 GBS guidelines call for laboratory evaluation of “at-risk” neonates, but the workup of these babies is not only costly, it does not provide any advantage over old fashioned clinical observation for the evaluation and treatment of early onset GBS sepsis. Objective . Multiple-dose metronidazole oral therapy is currently the reference treatment for bacterial vaginosis (BV). This double-blind, double-dummy, noninferiority study compared the e ﬃ cacy of secnidazole, another nitroimidazole with pharmacokinetics allowing a single dose regimen, to this standard treatment. Methods . A total of 577 patients were randomized to receive metronidazole (500 mg, b.i.d for seven days) or secnidazole (2g, once). Therapeutic cure at D28 was deﬁned as the resolution of vaginal discharge, positive KOH whi ﬀ test, vaginal pH > 4 . 5 and Nugent score > 7 on Gram-stained vaginal ﬂuid. Results . According to this primary endpoint, the single-dose secnidazole regimen was shown to be at least as e ﬀ ective as the multiple-dose metronidazole regimen (60 . 1% cured women vs 59 . 5% , 95% conﬁdence interval with a noninferiority margin of 10%: [ − 0 . 082;0 . 0094]). Safety proﬁles were comparable in both groups. Conclusion . The secnidazole regimen studied represents an e ﬀ ective, convenient therapeutic alternative that clinicians should consider in routine practice. Recent work on the Molicutes that associate with genital tract tissues focuses on four species that may be of interest in potential maternal, fetal, and neonatal infection and in contributing to adverse pregnancy outcomes. Mycoplasma hominis and Ureaplasma urealyticum have historically been the subject of attention, but Mycoplasma genitalis which causes male urethritis in addition to colonizing the female genital tract and the division of Ureaplasma into two species, urealyticum and parvum , has also added new taxonomic clarity. The role of these genital tract inhabitants in infection during pregnancy and their ability to invade and infect placental and fetal tissue is discussed. In particular, the role of some of these organisms in prematurity may be mechanistically related to their ability to induce inﬂammatory cytokines, thereby triggering pathways leading to preterm labor. A review of this intensifying exploration of the mycoplasmas in relation to pregnancy yields several questions which will be important to examine in future research. The incidence of preterm birth in developed countries has risen in the past decades. Underlying causes for this enigmatic pregnancy complication are numerous, yet infectious agents that induce dysregualtion of immunity at the maternal-fetal interface pose one of the most probable causes of preterm birth. This paper highlights two factors regarding maternal infections that trigger unscheduled inﬂammatory sequences that are deleterious to the maternal-fetal balance necessary to maintain pregnancy. Firstly, we discuss the role of Toll-like receptors (TLRs) as sentinels of uterine immunity in the context of response to pathogens. We highlight the idea that particular TLR activations lead to di ﬀ erential immune cascades that induce preterm birth. Secondly, two alternative routes of pathogenic entry may prove to be critical for inducing preterm birth via a cytokine storm or a secondary and currently unknown cell-mediated mechanism of uterine inﬂammation. This paper summarizes pathways that underlie activation of adverse and diverse immune responses to foreign agents that may result in preterm birth. in order to Data that systemic infections correlate to TNF- α -dependent immune responses that ultimately induce preterm birth. In contrast, intrauterine ascending infections occur when a pathogen ascends the uterine cavity via the vaginal tract. Surgical procedures in mice, rats, and rabbits have mimicked uterine cavity infections through intrauterine infusion of pathogens directly into the amniotic sac or between two placental units. Importantly, data summarized here demonstrate that pathogens introduced through intrauterine ascension do not tend to activate a TNF- α -driven axis to induce preterm birth. The objective of the study was to assess Plasmodium/intestinal helminth infection in pregnancy and other risk factors for stillbirth in Ghana. Methods . A cross-sectional study of women presenting for delivery in two hospitals was conducted during November-December 2006. Data collected included sociodemographic information, medical and obstetric histories, and anthropometric measures. Laboratory investigations for the presence of Plasmodium falciparum and intestinal helminths, and tests for hemoglobin levels were also performed. Results . The stillbirth rate was relatively high in this population (5%). Most of the stillbirths were fresh and 24% were macerated. When compared to women with no malaria, women with malaria had increased risk of stillbirth (OR = 1 . 9, 95%CI = 1 . 2–9.3). Other factors associated with stillbirth were severe anemia, low serum folate concentration, past induced abortion, and history of stillbirth. Conclusion . The fact that most of the stillbirths were fresh suggests that higher quality intrapartum care could reduce stillbirth rates. A range of schedules are recommended for hepatitis B vaccination of premature infants. This open-label study (217744/083) compared the immune response of premature ( N = 94) and full-term infants ( N = 92) to hepatitis B antigen following primary administration of hexavalent DTPa-HBV-IPV/Hib vaccine at 2–4–6 months and a booster dose at 18 months. Anti-HBsAg antibodies were determined before and one month after primary and booster doses. There were no signiﬁcant di ﬀ erences in postprimary seroprotection rates (anti-HBsAg > 10mIU/mL; preterm 93.4%; full-term 95.2%) or geometric mean concentrations (634 versus 867 mIU/ml), and neither appeared to be related to gestational length or birth weight. Prebooster seroprotection rates were 75 and 80.6%, respectively. Six premature infants did not respond to primary and booster doses. Primary and booster vaccinations with DTPa-HBV-IPV/Hib elicit satisfactory anti-HBsAg responses in preterm infants, which are not inﬂuenced by gestational age or birth weight. This schedule and vaccine will greatly facilitate the immunisation of premature infants.

epidemiologic, basic biomedical and clinical investigation on preterm birth, low birth weight, and numerous sequelae of untimely birth. As the problem has been examined from the expertise of various specialists and from separate but at times overlapping disciplines, different etiologic elements have emerged as important in the genesis of prematurity. Despite continuing discoveries in specific disciplines, preterm birth has not been etiologically tied to one factor such as genetic polymorphism, microbial challenge, or immune dysregulation. In recent years, the idea of "complex disease" has been proposed as a conceptual model for conditions that involve interplay between genetic, environmental, and other factors. This seems an apt description for preterm birth which will explain the breadth of topics in this special issue. This special issue begins by considering microbial challenges to successful pregnancy. Certainly, the concept of infectious disease as a factor in preterm birth and its sequelae must consider the microorganisms that inhabit the normal host and the way in which host immune system interacts with these microbes. The first five contributions to this issue are focused primarily on microbes that can threaten the pregnancy.
Foremost in understanding the microbial challenge to pregnancy is having the tools to appropriately characterize the maternal microbiome. In the paper by X. Zhou of Forney's laboratory, we are reminded that only since new, culture-independent, DNA-based methods of analysis have emerged we are able to correctly characterize the lower genital flora and establish that there is no longer one single list of microbes that can be called "normal." These findings provide important clarity to concepts regarding flora and preterm birth.
The second and third contributions in this series return to the problem represented by Group B Streptococcus (GBS). The concern for early identification and therapeutic intervention for GBS colonization in pregnancy has resulted in protocols that have become widely established. But experience over the past few decades has allowed a retrospective look at protocols again in specific clinical settings.
S. Faro et al. explore the experience of a private American hospital with respect to GBS screening and treatment. In 2 years of the study, they had an 89 percent screening rate with a 29 percent culture-positive rate with an invasive GBS incidence of 0.94 cases per 1000 live births. This is useful in underscoring the continuing need for vigilance for GBS.
The third paper in this issue, also on the topic of GBS, looks at the issue with neonates exposed or presumptively exposed to the organism. B. Buckler and coworkers suggest that some workup of asymptomatic neonates "inadequately treated intrapartum" may be more costly and no better than clinical observation and treatment as warranted. Clearly, clinicians continue to seek refinements to their approaches to individual pathogens, and while the approach to GBS may be seen by some as firmly established, some details of the approach to this organism in pregnancy are open to continued review and assessment.

Infectious Diseases in Obstetrics and Gynecology
Bacterial vaginosis is a topic that always emerges in discussions of preterm birth because of its epidemiologic association and the expansive literature that deals with the bacteriology and mechanistic associations with adverse pregnancy outcomes. Interest continues in finding antimicrobial approaches to the condition which in the case of the paper by I.-M. Bohbot and colleagues was aimed at clinical evaluation of secnidazole which they tested head to head with metronidazole.
The fifth paper continues the description of specific organisms of concern in infectious conditions that may threaten pregnancy. The cell-wall deficient bacteria, Mycoplasma and Ureaplasma, are frequently mentioned as having relationships to adverse pregnancy outcome, but in reality, these organisms are rarely cultured routinely in clinical practice. J. Hwang and B. Larsen have provided an update on the current understanding of these organisms in pregnancy and have reviewed research that reveals the important role of these microbes in eliciting cytokine responses that can be contributors to preterm birth.
The cytokine responses to Mycoplasma and Ureaplasma provide a nice segue into the sixth paper by J. E. Thaxton and coworkers. A cogent and timely summary of some of the important immune response mediators that can influence premature labor and delivery is provided as the conceptual connection between microorganisms and the immune responses that can lead to preterm birth. More specifically, this report provides a compelling account of the role of tolllike receptor engagement with intrauterine bacteria and the possibility of a cytokine storm involved in prematurity. The possible existence of a second uterine inflammatory pathway is an additional intriguing concept raised by this paper.
As a continuum from term birth to late preterm birth, early preterm birth is one that may consider the most significant result of infectious complications of pregnancy to be the loss of the baby, and pregnancy loss is a problem of international importance with some 4.5 million stillbirths occurring annually worldwide. Thus, it is fitting that this issue includes a paper that recognizes this problem and offers some hopeful information. A cross-sectional study of plasmodial and helminthic infections in Ghana is reported by N. Yatich and coworkers who found a higher risk of stillbirth among pregnant women with parasitic infection and suggested that some pregnancies might be salvaged with early intervention if these conditions can be recognized earlier.
The final paper in this issue by F. Omeaca et al. relates to the issues facing the preterm infant and one of the important threats to its survival and subsequent well-being. The authors explore the immune response of premature infants to hepatitis B vaccine as compared to term babies. In this report, while 6 of 94 premature infants did not respond, there were no significant differences in overall response to immunization due to low birthweight or gestational age suggesting the ability for vaccine application in this population.
The editors of this issue are pleased to offer paper that are not artificially focused but rather through the breadth of topics underscore the concept of complex disease mentioned at the beginning of this editorial. The complexity of genetics, immunity, and microbes acting in a tangled web of interactions reminds the reader why the issue of preterm birth has proven so intractable and why many different disciplines have something to contribute to the ultimate understanding of this clinical problem.
But we are hopeful that as the reader considers these varied contributions, it will be appreciated that despite the clinical descriptions and scientific discoveries, there is an underlying fact that deserves remembering. The clinical and scientific verities involved in adverse pregnancy outcomes are very personally felt by families that lose babies to infection or who have to deal with infants who are severely compromised by their prematurity. These parents undoubtedly are hopeful that the pursuits of scientists and physicians will move ever closer to practical answers to this very prevalent and vexing problem that intrudes on the happiness that is otherwise part of the birth of a child.