Low Preconception Complement Levels Linked to Adverse Pregnancy Outcomes in Antiphospholipid Syndrome

Sara Freeman

October 11, 2021

Low serum levels of two complement proteins are linked to worse pregnancy outcomes in women with antiphospholipid syndrome (APS), the results of a multicenter study appear to confirm.

The study evaluated preconception complement levels in 260 pregnancies in 197 women who had APS or were "antiphospholipid antibodies [aPL] carriers" and found that low levels of C3 and C4 in the 6 months prior to pregnancy were associated with several gestational complications and resulted in pregnancy losses.

"This study has validated, on large scale, the possible utility of preconception measurement of C3 and C4 levels to predict pregnancy loss in patients with aPL, even at a high-risk profile," said study investigator Daniele Lini, MD, of ASST Spedali Civili and the University of Brescia in Italy.

"The tests are easy and cheap to be routinely performed, and they could therefore represent a valid aid to identify women that need particular monitoring and management," he said at the 14th International Congress on Systemic Lupus Erythematosus (LUPUS 2021) held together with the 6th International Congress on Controversies in Rheumatology and Autoimmunity (CORA).

aPL and Adverse Obstetric Outcomes

aPL, which include lupus anticoagulant, anti-beta2 glycoprotein 1 and anti-cardiolipin antibodies, have been shown to induce fetal loss in animal models. Their influence on the outcome of human pregnancies, however, has been less clear, with several studies failing to prove a link between their presence and obstetric complications.  

Lini and co-investigators conducted a multicenter study involving 11 Italian centers and one Russian center, retrospectively looking for women with primary APS or women who had persistently high levels of aPL but no symptoms who had become pregnant. Of 503 pregnancies, information on complement levels before conception was available for 260, of which 184 had occurred in women with APS and 76 in women with persistently high aPL.

The pregnancies were grouped according to whether there were low (n = 93) or normal (n = 167) levels of C3 and C4 in the last 6 months.

"Women with adverse pregnancy outcomes showed significantly lower preconception complement levels than those with successful pregnancies, without any difference between APS and aPL carriers," Lini reported.

Comparing those with low to those with high complement levels, the preterm live birth rate (before 37 weeks' gestation) was 37% vs 18% (P < .0001).

The full-term live birth rates were a respective 42% and 72% (P < .0001).

The rate of pregnancy loss, which included both abortion and miscarriage, was a respective 21% and 10% (P = .008).

A subgroup analysis focusing on where there was triple aPL positivity found that preconception low C3 and/or C4 levels was associated with an increased rate of pregnancy loss (P = .05). This association disappeared if there was just one or two aPL present.

The researchers found no correlation between complement levels and rates of venous thromboembolism or thrombocytopenia.

Study Highlights "Impact and Importance" of Complement in APS

The study indicates "the impact and the importance of complement" in APS, said Yehuda Shoenfeld, MD, the founder and head of the Zabludowicz Center for Autoimmune Diseases at the Sheba Medical Center in Tel Hashomer, Israel.

In the early days of understanding APS, said Shoenfeld, it was thought that complement was not as important as it was in systemic lupus erythematosus (SLE). The importance of raised complement seen in studies of APS would often be discounted or neglected in comparison to SLE.  

However, "slowly, slowly" it has been found that "complement [in APS] is activated very similarly to SLE," Shoenfeld noted.

"I think that it's important to assess the component levels," Lini said in discussion. "This is needed to be done in the preconception counseling for APS and aPL carrier patients."

Determining whether there is single, double, or even triple aPL positivity could be useful in guiding clinical decisions.

"If we have triple positivity, that could mean that there may be a more immunologic activation of the system and that it could be useful to administrate hydroxychloroquine [to] those patients who would like to have a pregnancy," Lini suggested.

Plus, in those with decreased complement levels, "this could be a very useful tool" to identify where something could go wrong during their pregnancy.

The study had no outside funding. Lini and Shoenfeld have disclosed no relevant financial relationships.

14th International Congress on Systemic Lupus Erythematosus (LUPUS 2021) and 6th International Congress on Controversies in Rheumatology and Autoimmunity (CORA). Abstract presented October 8, 2021.

Sara Freeman is a UK-based medical journalist who specializes in medical conference reporting and content for websites. Follow her on Twitter @Sara_MedWriter.

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