Armed with this information, Dr. Salmon said, her team set out to identify factors that conferred the most risk during pregnancies for women with APS, lupus or both to design a trial for treatment of the women with the highest risk of complication. In the PROMISSE study (Predictors of Pregnancy Outcome in Systemic Lupus Erythematosus and Antiphospholipid Syndrome), researchers followed 755 pregnant patients with lupus, antiphospholipid antibodies or both, along with healthy controls, from 2003–2014.
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Overall, at least one adverse pregnancy outcome—including fetal death, neonatal death, preterm delivery or small size for gestational age—occurred in 19% of lupus patients. The factor conferring the highest risk was positivity for lupus anticoagulant, which had an odds ratio (OR) of 8.32 when compared with negative status. They also found that current antihypertensive drug use was one of the biggest predictors for such an outcome. Being non-Hispanic was protective (OR=0.45).3
The rate of an adverse pregnancy outcome was 58% among the 50 women known to be lupus anticoagulant positive—or who were lupus anticoagulant negative but non-white or Hispanic—and treated with antihypertensive medications. The rate of fetal or neonatal death was 22% among these patients.
The IMPACT Trial
In the IMPACT trial (Improve Pregnancy in APS with Certolizumab Therapy), a phase 2 open-label study, the TNFα blocker certolizumab was added to a regimen of heparin and low-dose aspirin in high-risk pregnancies in women with clinical APS—with or without lupus—and persistently positive for lupus anticoagulant.
Based on data from the PROMISSE trial, the expectation was that 44% of these pregnancies would have an adverse outcome of fetal death at greater than 10 weeks’ gestation or preterm delivery at less than 34 weeks due to preeclampsia and placental insufficiency. Certolizumab is already approved for treatment of rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis and Crohn’s disease, and isn’t transferred across the placenta.
Doses of certolizumab were similar to those used in RA and Crohn’s disease, with the first dose at eight weeks and six days of gestation to target abnormal development of the placenta, which starts early and is usually found at 12–15 weeks. Certolizumab is discontinued at 28 weeks, after which benefit is unlikely.
With a trial target of 50 participants, 27 patients have been enrolled, 23 of whom have completed pregnancies that can be evaluated. Only three—or 13%—of the women experienced a primary outcome, far lower than the 44% expected. One fetal death occurred at 10.3 weeks of gestation, along with two cases of preeclampsia with births at less than 34 weeks.