Biomarkers Can Help Determine Lupus Patients At Risk During Pregnancy

Jane E. Salmon, MD Division of Rheumatology Hospital for Special Surgery, and Weill Cornell Medical College, New York, NY Interview with:
Jane E. Salmon, MD
Division of Rheumatology
Hospital for Special Surgery, and
Weill Cornell Medical College, New York, NY 

Medical Research: Background on lupus and antiphospholipid antibodies – what are they?
Dr. Salmon: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease that predominantly affects women and presents during their childbearing years. In SLE, the immune system which normally protects one from infection, turns reacts against the self and can cause damage of multiple organs.

Antiphospholipid antibodies (APL) occur in some people with SLE and some without SLE. They are autoantibodies that can damage the placenta and cause arterial and venous thromboses. Patients with APL can have fetal deaths, miscarriages, preeclampsia and/or growth restricted babies.

Pregnancy in patients with SLE, particularly those with antiphospholipid antibodies (APL), and in patients with APL alone, is associated with an increased risk for maternal and fetal morbidity due to preeclampsia (PE) and insufficient placental support of the developing fetus. PE and placental insufficiency are, in turn, associated with adverse pregnancy outcomes (APOs), including maternal complications of PE, intrauterine fetal death, and fetal growth restriction, as well as indicated preterm delivery. Given that APOs affect over one fifth of pregnancies in SLE and/or APL, the ability to identify patients early in pregnancy who are destined for poor outcomes would significantly impact care of this high risk population.

Medical Research: Two bullets about your PROMISSE study:

Dr. Salmon: The PROMISSE Study (Predictors of pRegnancy Outcome: bioMarker In antiphospholipid antibody Syndrome and Systemic lupus Erythematosus). PROMISSE is the largest multi-center, multi-ethnic and multi-racial study to prospectively assess the frequency of APO, clinical, laboratory and biomarker variables that predict APO, in women with SLE and/or APL with inactive or mild/ moderate activity at conception.

Pregnant patients with SLE and/or APL were enrolled at <12 weeks gestation into PROMISSE between September 2003 and August 2013 at 7 sites (n=497) along with matched healthy controls (n=207) and followed every month of pregnancy. 

Medical Research: Why study angiogenic and anti-angiogenic factors in these patients?

Dr. Salmon: Biomarkers altered early in pregnancy are needed to identify, counsel and manage patients at high risk of APOs.

Prospective studies in otherwise healthy women demonstrate angiogenic dysregulation up to 5 weeks before clinical manifestations of PE, a time too late to intervene.

An imbalance between circulating antiangiogenic and proangiogenic proteins is also associated with fetal growth restriction and death in non-autoimmune patients.

We found that circulating angiogenic factors measured during early gestation have a high negative predictive value in ruling out the development of severe adverse outcomes among patients with SLE and/or APL syndrome. Timely risk stratification of patients is important for effective clinical care and optimal allocation of healthcare resources.

Medical Research: What are the key findings of the study for laypeople?

Dr. Salmon: Pregnancies in patients with SLE and/or aPL can result in poor outcomes, even when disease activity is low, and baseline clinical features and laboratory tests have only modest ability to identify patients at highest risk for APOs. Our study is the first to demonstrate, in a prospective cohort, the usefulness of angiogenic biomarkers measured as early as the 12th week of pregnancy, in combination with clinical criteria, to identify patients with SLE and/or APL at risk of severe APO.

Currently, most SLE and APL patients undergo extensive antenatal evaluation, including serial obstetrical ultrasound exams and multiple visits to rheumatologists and obstetrician. We have identified important prognostic factors that can be used by physicians to identify those at low and high risk of severe APOs.   The majority of lupus and/or APL women would be identified as being at low-risk for severe adverse outcomes and in this group the number of medical visits could be substantially reduced. Patients at low risk can be reassured and healthcare costs for their pregnancies decreased, whereas those at high risk can be managed by specialists with close monitoring and delivery for severe maternal and/or fetal disease.

The findings of the study allow physicians stratify risk early in pregnancy to optimize patient care and allocation of healthcare resources. If angiogenic biomarker levels remain normal, we can reassure patients that fewer than 5 out of 100 will not develop serious complications, such as preeclampsia, severe growth restriction or fetal death. When these biomarker tests are available clinically, they will guide prenatal care in pregnant women with SLE and/or APL. 

Dr. Salmon: What are the recommendations for future research as a result of this study?

Dr. Salmon: The goal of our research efforts is to provide early identification of risk in expectant mothers with lupus and to develop treatments to prevent serious pregnancy complications. We are halfway there. Our findings provide the basis for identifying high risk pregnancies for enrollment in future trials that target pathways upstream or downstream of angiogenic factors, sufficiently to prevent APOs.   And we are now planning a trial with a drug that targets the mediators of placental injury in such patients.


Jane E. Salmon, MD et al. Angiogenic Factor Imbalance Early in Pregnancy Predicts Adverse Outcomes in Patients with Lupus and Antiphospholipid Antibodies: Results of the PROMISSE Study.American Journal of Obstetrics & Gynecology, September 2015 DOI:10.1016/j.ajog.2015.09.066

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Jane E. Salmon, MD (2015). Biomarkers Can Help Determine Lupus Patients At Risk During Pregnancy