Preterm Labor and Intraamniotic Infection (IAI): serious complications to pregnancy with potentially significant consequences

Preterm labor can be defined as regular contractions associated with cervical change that occur before 37 weeks of gestation and can be caused by a range of different conditions. The most common causes of preterm labor are intraamniotic infection (IAI), premature rupture of fetal membranes and multi-fetal gestations.

Intraamniotic infection, which is also sometimes referred to as amniotic fluid infection or chorioamnionitis, is a serious infection of the amniotic fluid and surrounding fetal membranes and has been identified as a major cause of preterm birth. IAI accounts for up to 10-20% of all preterm deliveries and 50% of preterm deliveries before 30 weeks. ¹

This diagram shows the presence of infection in the amniotic fluid, surrounding membranes, cervix and vagina:



Risks of Intraamniotic Infection
IAI is also associated with increased risk of serious infectious complications including death, for both pregnant women and their newborn babies.

IAI creates a hostile environment for both the fetus and the pregnant woman; the longer IAI remains untreated, the more serious the potential outcome. Some of the most critical complications for a newborn infant associated with IAI are neonatal sepsis (the presence of infectious organisms such as bacteria in the blood), respiratory distress syndrome, bleeding within the brain and death. Some of the most critical complications for pregnant women associated with IAI are infection of the uterus and other reproductive organs, sepsis and death.⁵

IAI can be difficult to detect and diagnose because it frequently occurs with little or no clinical symptoms other than the sudden onset of preterm labor. The risk of IAI in association with preterm labor is inversely related to gestational age—the earlier the onset of preterm labor, the more likely that infection is responsible. Intraamniotic infection is less common beyond 34 weeks of gestation.

IAI increases the risk of serious complications for the baby if left untreated. IAI is associated with one third of early-onset neonatal sepsis cases, a clinical condition in which microorganisms enter the blood of the baby and may profoundly affecting body systems potentially causing pneumonia, hemorrhage or bleeding within the ventricles of the brain and seizures.⁶ IAI also accounts for the highest proportion of neonatal death in the United States.⁶ A meta-analysis of 19 published studies has also demonstrated a clear link between IAI and cerebral palsy.⁸

Treatment of Intraamniotic Infection
Appropriate management of preterm labor requires knowledge of whether or not IAI is present.

Intraamniotic infection can be reliably treated when it is detected. Antibiotics administered intravenously to women during labor cross the placenta and are able to treat bacteria within the fetus and surrounding amniotic fluid.²³

Studies in pregnant women with IAI who are treated with antibiotics before delivery have shown significantly lower rates of neonatal sepsis, neonatal death and shorter hospital stays for both mothers and newborn infants, as compared to when antibiotic treatment is started after delivery.²⁴ In addition, early diagnosis of IAI allows transport of the mother to a delivery location with an appropriate level of care such as a Neonatal Intensive Care Unit (NICU) and also facilitates optimal timing for delivery of the baby.

If IAI is not present, a range of different treatment strategies can be utilized to slow or stop preterm labor and attempt to maintain the pregnancy as long as possible.

Determining the presence or absence of IAI in preterm labor, allows clinicians to determine and implement optimal treatment strategies. However, managing preterm labor without a clear knowledge of whether IAI is present can create clinical challenges. For example, tocolytic drugs, used to slow or stop preterm labor, are appropriate treatment in the absence of IAI, but may cause maternal complications if used when IAI is present.²⁵ In the same way, antibiotic therapy used to treat infection assuming IAI is present, may increase the risk of neonatal complications and development of antibiotic resistant organisms, if used when IAI is not present.²⁶

Conventional Methods for the Detection of IAI
Detection of IAI may be difficult as 80% to 90% of all cases occur without clinical symptoms.²

Currently, the definitive method to identify IAI in preterm labor is via laboratory tests performed on amniotic fluid that is obtained via amniocentesis. Amniocentesis is a procedure that is performed by inserting a small needle through the abdominal wall and into the uterine cavity to collect a sample of amniotic fluid surrounding the fetus. The amniocentesis procedure is typically performed using ultrasound imaging to guide placement of the needle. The amniotic fluid is then tested in a laboratory to help determine if microorganisms are present.

Amniocentesis is an important tool in evaluating the risk of IAI in patients with preterm labor. However, currently available amniotic fluid laboratory diagnostic tests and the amniocentesis procedure itself have limitations. One limitation is that it can typically take as long as 48 hours for a clinician to receive microbial culture results; one of the most important and common laboratory tests for detection of IAI. Microbial culture is a method of enhancing growth of organisms that may be present in amniotic fluid, by promoting their reproduction in culture media under controlled laboratory conditions. Microbial cultures are used to determine if infectious organisms are present, the types of organisms present and relative abundance in the sample being tested.

72 hours are typically required to obtain the results of amniotic fluid culture testing and this delay can limit this test’s usefulness in the management of preterm labor. In many cases of preterm labor, a clinician will need to make treatment decisions before culture test results are available. Results from other laboratory tests performed on the amniotic fluid obtained by amniocentesis, such as Gram stain and measurement of glucose concentrations, can be available more quickly than microbial culture, but are less accurate for detecting IAI.

Given the frequent absence of clinical symptoms and limitations of current IAI diagnostic tests, assessing the risk for IAI in preterm labor patients is currently problematic.

Molecular Diagnostic Technologies Provide New and Improved Tools for Detecting Intraamniotic Infection
Historically, microbial culture of amniotic fluid has been recognized as the “gold standard” for the detection of intraamniotic infection. However, this culture-based approach for detection of IAI has a number of disadvantages:

• Microbial detection and identification via culture depends on growth conditions favorable to a select group of known microorganisms. Consequently, difficult-to-cultivate or uncultivatable bacteria will not be detected by culture alone.¹² Mycoplasma and Ureaplasma species are two of the most common bacteria that cause IAI (present in 30% to 50% of cases) and are also difficult to cultivate. Tests to detect these pathogens are not commonly available in most laboratories.

• 48 to 72 hours are needed for complete amniotic fluid results; in many cases of preterm labor, this may be too long for the test results to be useful in determining the optimal treatment and clinical management strategy.

• In addition, antibiotic use prior to obtaining amniotic fluid for laboratory testing can reduce or eliminate the ability of culture to detect pathogenic organisms.

State-of-the-art molecular microbiology techniques such as Polymerase Chain Reaction (PCR) can detect infectious microorganisms independently of culture. PCR identifies IAI by detecting and quantifying in amniotic fluid specific genes in the DNA of infectious organisms such as bacteria and fungi. By detecting DNA that is uniquely characteristic of individual infectious organisms, PCR can identify IAI faster and more accurately than amniotic fluid microbial culture alone:

• Numerous published clinical studies using laboratory testing of amniotic fluid to detect intraamniotic infection, have reported that PCR tests have identified 30%-50% more cases of IAI than culture alone.¹³

• The speed of PCR test results are not limited by the organic growth rate of microorganisms, therefore PCR can provide test results detecting the presence or absence of IAI in amniotic fluid within 24 hours, instead of the 48 to 72 hours typically needed for amniotic fluid culture.

Because PCR provides physicians a faster and more accurate tool for determining the presence or absence of IAI, clinicians are able to more quickly and accurately identify the most appropriate treatment for IAI in preterm labor.

ProteoGenix is the first and only company to offer a commercially available 16S rDNA Endpoint PCR test in amniotic fluid for the detection of bacterial, Mycoplasma and Ureaplasma species DNA to aid in the clinical diagnosis of IAI.