Why don’t all women develop inflammation?
A critical question is why some pregnant women with microbial invasion of gestational tissues develop inflammation, whereas others do not. Susceptibility depends, in part, on the pathogenicity and amount of invading bacteria. Endotoxin-containing gram-negative bacteria elicit an especially potent inflammatory response. The strength of the response correlates with the amount of endotoxin-containing bacteria in the environment.7
The isolation rate of bacteria from the intrauterine cavity is higher in women with bacterial vaginosis (BV), a condition characterized by malodorous vaginal discharge, vaginal pH higher than 4.5, and a shift from a Lactobacilli-dominant vaginal flora toward predominance of G vaginalis, anaerobic bacteria, and M hominis. The greater number of bacteria may account, in part, for a twofold greater risk of preterm delivery among women diagnosed with BV during pregnancy.8
Genetics may also play a role. Intrauterine inflammation and morbidity are partly influenced by common variations (polymorphisms) in immunoregulatory genes. Preliminary evidence suggests that some women who carry a variant of the TNF-α gene can mount an exaggerated immune response to BV-related organisms (hyper-responders),9 increasing their risk of preterm delivery.10
Inflammation alone is a risk factor for CP
Growing evidence suggests that intrauterine inflammation increases the risk of neonatal white matter disease and subsequent development of CP beyond the risk conferred by gestational age at birth. The relative risk (RR) for CP in preterm infants born after intrauterine infection and inflammation or inflammation alone is 1.9 and 1.6, respectively.11
The association between inflammation, neonatal white matter disease, and CP is strongest in fetuses with funisitis and a plasma IL-6 level greater than 11 ng/mL12—a condition known as fetal inflammatory response syndrome (FIRS). FIRS is also associated with other sequelae of prematurity, including bronchopulmonary dysplasia, respiratory distress syndrome, and myocardial dysfunction.
Can we diagnose subacute inflammation and infection?
Diagnosing and treating intrauterine inflammation promptly may decrease the risk of CP. No single sign, symptom, or test accurately predicts intrauterine infection and inflammation in the pregnant patient. Maternal signs and symptoms such as fundal tenderness, tachycardia, and fever, along with laboratory findings such as an elevated C-reactive protein level and an elevated white blood cell (WBC) count in peripheral blood, indicate overt chorioamnionitis and systemic maternal infection. However, these tests are not especially useful for diagnosing subacute intrauterine infection and inflammation in patients with preterm labor and intact membranes or pPROM. Some authorities advocate amniocentesis for these patients.
Cerebral palsy: Key preventive measures reflect disease origins
- Prematurity is the leading risk factor for cerebral palsy (CP)
- Subacute intrauterine infection and inflammation are common causes of preterm delivery
- Intrauterine inflammation may lower the threshold at which hypoxia becomes neurotoxic in the fetus
- No single sign, symptom, or test accurately predicts intrauterine infection and inflammation in the pregnant patient
- A biophysical profile (BPP) score of 7 or lower predicts infection-related neonatal outcomes better than any single component of the BPP
- In a pregnancy complicated by pPROM, adjunctive antibiotics prolong pregnancy for as long as 10 days, but do not affect neonatal neurologic outcome
- Adjunctive antibiotics have no proven benefit in managing preterm labor with intact membranes
- Screening for and treating bacterial vaginosis during pregnancy are not useful
- Prophylactic antibiotic treatment during the periconceptional period has no proven benefit
- A single course of antenatal steroids in preterm labor with intact membranes or pPROM significantly decreases neonatal mortality and neurologic morbidity without raising the risk of neonatal sepsis—even in the presence of intrauterine infection
- Tocolysis with magnesium sulfate or a calcium-channel blocker to stop preterm labor with intact membranes may decrease neurologic morbidity in neonates
- Consider delivery after 32 weeks if fetal lung maturity is confirmed because 1) expectant management of pPROM beyond 32 completed weeks of gestation does not have a clear benefit and 2) intrauterine inflammation associated with white matter disease is common in pPROM
A positive bacterial culture or gram-stained slide of amniotic fluid confirms intra-amniotic infection but detects fewer than 50% of cases. Other diagnostic criteria, such as an elevated WBC count, high level of lactate dehydrogenase activity, high protein level, and low glucose concentration in amniotic fluid, are more sensitive, but nonspecific, for amniotic infection and inflammation.
Elevated inflammatory cytokines such as IL-6 in amniotic fluid and fetal blood have been associated with intrauterine inflammation and neonatal white matter disease in women with preterm labor and intact membranes or pPROM, but they are not significantly more accurate than the previously mentioned biomarkers.13,14 An amniotic fluid pocket may not be accessible by the abdominal approach in most patients with pPROM because of significant oligohydramnios. Testing amniotic fluid from the vagina is an alternative. Low glucose in vaginal samples is a specific, but not a sensitive, marker for intra-amniotic infection.15