The Role of Infection

In terms of the amniotic fluid glucose concentration, under normal circumstances glucose is present in the amniotic fluid. The lower the amniotic fluid glucose value, the higher the likelihood of intraamniotic infection or inflammation. For example, glucose values less than 14 mg/dL in women with intact membranes—or less than 10 mg/dL in women with preterm PROM—suggest that intraamniotic infection and/or inflammation is present.

EAR: Are there other tests, such as measurements of cytokines or other proteins, that can be used to detect inflammation in the amniotic fluid?

RR: The concentrations of a cytokine, such as interleukin-6, can be used to detect inflammation. Similarly, we have developed a rapid test that can be used at the bedside to detect inflammation by detecting the concentration of an enzyme produced by neutrophils. This enzyme is MMP-8 (matrix metalloproteinase-8).

These tests can be valuable in the context of midtrimester amniocentesis. The rate of pregnancy loss after a midtrimester amniocentesis has been estimated to be 0.5%–1%; such losses have mistakenly been thought to be always procedure related. However, we have found that among women who have midtrimester amniocenteses, those who have an elevated IL-6 or MMP-8 concentration are more likely to lose their pregnancy or have a spontaneous abortion shortly after the procedure. In these circumstances, determination of IL-6 or MMP-8 in the amniotic fluid stored by the genetic laboratories may be helpful for the patient and physician to identify that intraamniotic inflammation was a cause of the pregnancy loss. This may also have medicolegal implications.

EAR: How common is intraamniotic infection and/or inflammation in women having genetic amniocenteses in the midtrimester of pregnancy?

RR: The frequency of intraamniotic infection has been estimated to be 0.9%; the frequency of intraamniotic inflammation is about 1.2%. The most common organism found in the amniotic fluid is U. urealyticum. Intraamniotic infection and/or inflammation is more common in women who have discolored amniotic fluid at the time of genetic amniocentesis. It is important to realize that these infections are subclinical and that sometimes, patients with these infections rupture their membranes within hours or days of the procedure.

EAR: Can treatment be offered to these patients with midtrimester intraamniotic infections?

RR: Recent evidence from Dr. Sonia Hassan in our group indicates that the administration of antibiotics to the mother can eradicate intraamniotic infection in the midtrimester. Women with a short cervix detected by ultrasound were found to have microorganisms in 9% of cases. Patients were offered treatment with antibiotics and a repeat amniocentesis was performed to be sure that the infections were eradicated. Most women treated in this fashion had eradication of their intraamniotic infection and their pregnancy went to term.

EAR: How frequently are intrauterine infections confined to the amniotic fluid, and how often is the fetus involved?

RR: A study conducted in the United Kingdom in women with preterm PROM indicated that approximately 30% of patients had microorganisms in the amniotic fluid. Of these, 30% had positive fetal blood cultures. This means that 10% of all fetuses with preterm PROM will have fetal bacteremia. Clearly, this represents a minimum estimate of the frequency of fetal infection, a result of the limitations of standard techniques and the difficulties in isolating relevant microorganisms from fetal blood.

EAR: What is the importance of congenital neonatal infections?

RR: Sepsis is a more serious disease in neonates than in adults. Neonates have been generally considered immunosuppressed hosts, and the lethality of sepsis in neonates is high. There is now accumulating evidence that neonates with sepsis are more likely to develop cerebral palsy and bronchopulmonary dysplasia or chronic lung disease.

EAR: How important is intrauterine infection as a cause for cerebral palsy?

RR: It has been estimated that as many as 20% of all cases of cerebral palsy result from infection. Moreover, this applies to term neonates as well as to preterm neonates. Therefore, the traditional paradigm—that intrapartum asphyxia was the leading cause of cerebral palsy—is probably not correct. Obstetricians need to be aware that undiagnosed infections can be a cause for cerebral palsy because this has medicolegal implications.

EAR: What is the link between infection and the brain injury associated with cerebral palsy?

RR: Microorganisms involved in cases of intraamniotic infection can invade the human fetus. When the fetus breathes or swallows infected amniotic fluid, microorganisms may be entering the fetal compartment. Once microorganisms invade the fetus, they elicit a fetal inflammatory response syndrome (FIRS), which is the counterpart of the systemic inflammatory response syndrome (SIRS) in the adult. In FIRS one of the most critical organs affected is the brain. Microorganisms or their products that gain access to the fetal brain can induce damage of neurons or white matter in utero. Damage to the white matter in utero is also known as periventricular leukomalacia (PVL) and is the most important predictor of cerebral palsy. There is evidence that cytokines, chemokines, and other inflammatory products—such as reactive oxygen metabolites—can cause damage to the glia or to neurons, which is responsible for the cognitive abnormalities, including mental retardation.