For those of you who are just joining us, I have been posting a series on preterm birth (PTB) because of the magnitude and epidemic growth of the problem in the U.S. today. In the last post, we began a discussion of broad categories of risk factors. The last major categories I usually discuss with patients are infection and inflammation. In the big scheme of things, these are our greatest concerns. Not only are they the most common factors associated with 'spontaneous' PTB, but they also tend to result in the earliest deliveries and are involved in well more than half the PTBs before 32 weeks' gestation. When present, they are also associated with the greatest risk of short- and long-term morbidity for the baby.
The biochemical factors accompanying both infection and inflammation (either 'sterile' or that secondary to infection) are major contributors to the "final common pathway" of preterm labor by their diverse effects on the uterus, cervix and fetal membranes. There are a multitude of inflammatory mediators that can directly or, indirectly, by the induction of other factors such as prostaglandins, increase uterine contractility and promote cervical 'ripening.' The latter represents a transition in the composition and arrangement of connective tissue and 'ground substance' in the cervix that ordinarily is delayed until late in pregnancy, immediately preceding, or accompanying the onset labor.
In today's post, let's focus on infection. Again, for the sake of simplicity, I usually break down problems related to infection into those that are extrauterine (outside the uterus), involving anatomic structures in proximity to the uterus (bladder, bowel, cervix, and vagina), and those that are the source of secondary infection of the uterine contents. Secondary intrauterine infection can result either from initial infections of those same anatomic structures in proximity to the uterus or from infections (clinically evident or not) at other sites outside the abdomen and pelvis. It should be noted that production of inflammatory mediators can arise, depending on the organism involved, as a consequence of local tissue damage, of chemicals produced by the organisms themselves, and from nonspecific and specific immune responses to the unwelcome organisms. When high fever accompanies an infection, it may not only reflect the systemic (blood borne) presence of inflammatory mediators, but may also potentiate their action on the uterus and cervix.
The most common 'infections' we see are those caused by bacterial organisms. Many of the bacteria associated with PTB are those with which women are chronically colonized in the gastrointestinal tract or vagina. For example, during pregnancy, women are at greater risk for urinary tract infections (subject for another post). Many of the bacteria that commonly cause bladder and kidney infections, such as E. coli and Klebsiella, are normal inhabitants of the colon. The bladder sits right on top of the cervix and lower portion of the uterus. When an infection occurs in the bladder, either symptomatically or subclinically, local release of inflammatory mediators and prostaglandins may induce uterine contractions and cervical ripening which, in some instances, can progress completely unperceived by the pregnant woman until advanced, usually, irreversible changes have taken place. Although not completely understood, it is thought that the inflammatory mediators reach the uterus and cervix by direct diffusion across contiguous tissues or via transfer in common blood or lymphatic channels. It is also possible local irritation of nerve-endings in the bladder causes a more generalized activation of nerves, also enervating adjacent structures, that may initiate uterine contractions.
Although it is not feasible to discuss all of the different situations in which infection may play a role, several other scenarios can illustrate the spectrum of conditions by which infection may contribute to PTB. Gastrointestinal infections with pathogenic bacteria and, more commonly, viruses, particularly those that are accompanied by cramping and diarrhea, place the pregnant woman doubly at risk. The 'cramping' reflects conditions under which smooth muscle contractility again is increased (remember both the bowel and the uterus are made up of smooth muscle) and the diarrhea can result in dehydration and electrolyte imbalances that are independent risk factors for increased uterine activity. When fever is present, as is often the case with GI infections, this may enhance both the rate and severity of dehydration.
Other local infections, varying in severity and chronicity, can also be the source of inflammatory mediators. Examples of these include common cervical, urinary tract, and rectovaginal infections such as Trichomonas, Chlamydia, Neisseria gonorrhea, Mycoplasma, 'bacterial vaginosis,' and Group B ?-hemolytic Streptococcus, and even 'yeast,' all of which may be asymptomatic, or minimally so, during pregnancy. Of these conditions, women who develop bacterial vaginosis, a shift from the normal vaginal flora to overgrowth of more pathogenic bacteria, may be at greatest risk for PTB. In contrast to these more indolent conditions, acute severe herpes simplex virus (HSV) infections, usually primary infections in women with no prior immunity to HSV, can cause intense tissue damage of the cervix, vagina, and vulva that is typically accompanied by production of large amounts of inflammatory mediators, locally, as well as systemically. Recurrent HSV infections probably are not a significant cause of preterm labor.
Primary infections at any of the sites mentioned above have the potential to infect, secondarily, the uterine contents including the placenta, the fetal membranes, or the baby and the amniotic fluid. Such infection can spread to the uterine contents by either hematogenous (blood-borne) or lymphatic channels or by direct extension from the site of infection, most often the result of ascending infection through the cervix. Of the blood-borne infections, kidney infections (pyelonephritis) and, most recently recognized, periodontal infections are probably the most common contributors. Of the ascending infections, pathogenic organisms associated with bacterial vaginosis, including a plethora of 'anaerobic organisms' that proliferate in the absence of oxygen, are perhaps the greatest offenders. Indeed, the earlier the preterm birth, the greater the likelihood that these organisms will be involved in either overt or subclinical intrauterine infections.
There are certainly many other mechanisms by which infection can result in PTB, for example, by causing fetal malformations, anemia, tissue damage (and inflammatory mediator release), and placental insufficiency, just to mention a few. But, overall these comprise only a small portion of PTBs and the complexity of the explanations required would only detract from the big picture we are trying to present here. So, let's stop for today and in our next post (or perhaps the one after), we will finish up discussing risk groups for PTB with an important, but poorly understood, category, that being inflammation not related to infection...