Normal pregnancy is characterized by systemic activation of the complement system

Abstract

Background: The complement system, a major component of innate immunity, has recently been implicated in the mechanisms of fetal loss and placental inflammation in the anti-phospholipid antibody syndrome. Inhibition of complement has been proposed as an absolute requirement for normal pregnancy. Yet, pregnancy is characterized by a generalized activation of the innate immune system. This study was conducted to determine whether or not normal pregnancy is associated with complement activation in the maternal circulation.

Methods: Anaphylatoxins (C3a, C4a and C5a) were determined in the plasma of normal pregnant (20-42 wks; n=134) and non-pregnant women (n=40). These complement split products (C3a, C4a and C5a) were measured using specific immunoassays. Non-parametric statistics were used for analysis.

Results: 1) The median plasma concentrations of C3a, C4a and C5a were significantly higher in normal pregnant women than in non-pregnant women (all p<0.001); 2) the concentration of C3a, C4a and C5a did not change with gestational age (p>0.05); and 3) the median plasma concentration of C3a had a positive correlation with the plasma C4a and C5a concentrations (r=0.36, p<0.001 and r=0.35, p<0.001, respectively).

Conclusion: 1) Normal human pregnancy is associated with evidence of complement activation, as determined by higher concentrations of the anaphylatoxins C3a, C4a and C5a in the maternal circulation; and 2) we propose that physiologic activation of the complement system during pregnancy is a compensatory mechanism aimed at protecting the host against infection.

Figure 1

Plasma anaphylatoxin concentrations in non-pregnant and pregnant women. Please note the difference of the scales on the y-axis between A, B and C. A, The median plasma concentration of C3a was higher in normal pregnant women than nonpregnant women (median 2364.7 ng/ml, range 557.9 – 6642.7 ng/ml vs. median 1340.4 ng/ml, range 367.4 – 6722.4 ng/ml; p<0.001). B, Normal pregnant women had a median plasma C4a concentration higher than nonpregnant women (median 10125.4 ng/ml, range 850.7 – 32640 ng/ml vs. median 2625.4 ng/ml, range 304 – 21380 ng/ml; p<0.001). C, Normal pregnant women had a median plasma C5a concentration higher than nonpregnant women (median 12.4 ng/ml, range 1.2 - 87.1 ng/ml vs. median 4.1 ng/ml, range 0.9 - 13.1 ng/ml; p<0.001).

Figure 2

Relationship between plasma anaphylatoxin concentrations and gestational age. In normal pregnant women, the plasma C3a, C4a and C5a concentrations did not show a correlation with advancing gestational age from 20 weeks to term (C3a r = −0.16, P=0.05; C4a r = −0.08, P=0.35 and C5a r = 0.15, P=0.08).