Abstract: Preterm birth affected 1 of every 10 infants born in the United States and researches show that it is highly related to complement system, through which, scientists are trying to find how to predict and prevent preterm birth.
Preterm birth is a syndrome caused by many factors such as infection, excessive dilation of the uterus, stress, drug abuse, and neuropsychiatric diseases. At present, the mechanism involved in initiating this process is unclear, but infection and inflammation are highly related to preterm birth, accounting for 25% to 40% of preterm birth cases.
The complement system, playing an important role in the inflammatory response caused by infection, is a natural immune mechanism that consists of more than 50 blood proteins. In general, the activation level of the complement system is relatively low. After activation, it triggers a series of enzymatic reactions to drive the inflammatory response and eventually eliminates pathogens.
Depending on the activation triggers, the complement system can be stimulated by three distinct pathways: the classical, lectin and alternative pathway. Disorders of the complement system can trigger excessive inflammatory responses and cause damage to tissues.
Complement components are mainly synthesized by the liver, but can also be synthesized in a variety of tissues including the placenta. A fully functional complement system is essential for maintaining host defense and protecting the fetus and mother from infection.
For example, the complement component 1q (C1q) is a protein complex that is involved in the complement cascade. C1q-knockout mice show abnormal placental development and spiral arterial remodeling, which leads to the reduced number and weight loss of litter, while showing preeclampsia-like phenotypes, such as high blood pressure and proteinuria. This study indicates that C1q is critical for pregnancy.
Other studies have found that complement activation fragments (such as C3a/ Bb) in circulating blood of preterm patients are significantly increased. Genetic defects in complement regulatory factors (such as CD55) will lead to over-activation of complement and recurrent miscarriage. In addition, there is increasing evidence showing that genetic mutations in complement regulatory proteins are prone to adverse pregnancy outcomes such as preterm birth.
Since scientists have found the association between complement activation and adverse pregnancy outcomes, how can we use it in maternal healthcare?
Research has found that adverse pregnancy outcomes in pregnant women with high levels of C3a are 3 times more than that in women with lower levels of C3a. Similarly, after controlling other preterm birth-related risk factors, those with elevated levels of Bb in early pregnancy are almost 4 times more likely to suffer preterm birth than the normal group, indicating that increased C3a or Bb as a predictor of preterm birth has great potential.
Regulation of complement activation can reduce its harmful effects on maternal and newborn infants. Currently, related targeted therapeutics can work by preventing complement activation or suppressing the result of activated complement components. However, whether these can be applied to pregnant women and how to evaluate the dose still need to be answered.
In terms of complement imbalance and preterm birth, more research is necessary in assessing biomarkers that can be used to predict various adverse pregnancy outcomes resulting from complement overactivation or complement deficiency. In addition, scientists are still trying to find out how to control complement activation to a certain level that can ensure the natural defense of the host, as well as the safety of infants.