# TNF-alpha Blockade with Certolizumab to Prevent Pregnancy Complications in High-Risk Patients with APS

> **NIH NIH R21** · HOSPITAL FOR SPECIAL SURGERY · 2020 · $196,279

## Abstract

Project Summary/Abstract
Antiphospholipid syndrome (APS) is an autoimmune disorder that occurs most commonly in women of
reproductive-age and is associated with thrombosis and adverse pregnancy outcomes (APOs), such as fetal
loss and preterm birth due to severe preeclampsia (PE) or placental insufficiency (PI). The diagnosis of APS
requires the presence of antiphospholipid antibodies (aPL), including the lupus anticoagulant (LAC). Therapy
for APS focuses on preventing thrombosis, but thromboprophylaxis has not effectively prevented poor
pregnancy outcomes. In PROMISSE, a prospective multicenter observational study of 724 patients, 44% of
pregnancies in women with APS and LAC resulted in APOs despite treatment with heparin and low dose
aspirin. Angiogenic dysregulation early in pregnancy predicted APOs, most of which were due to failure of
adequate vascularization of the developing placenta and underperfusion of the fetus. Mouse models show that
poor placental vascularization in APS is due to inflammation: aPL target placental tissue, and activate
complement, leading to recruitment of neutrophils and release of inflammatory mediators and anti-angiogenic
factors. We found that TNF-α was a critical downstream effector of abnormal placental development and fetal
damage, and that TNF-α blockade restored angiogenic balance, normalized placentation and spiral artery
remodeling, and rescued pregnancies. Based on our observations in PROMISSE and the favorable results of
TNF-α blockade in our mouse models, we hypothesize that TNF-α blockade will significantly decrease the rate
of preterm delivery due to PE and PI in women with APS and LAC. With the infrastructure created for
PROMISSE, we are poised to conduct the first trial of a biologic therapy to prevent APOs in high-risk APS
pregnancies. Our specific aims are to determine whether TNF-α blockade during pregnancy, added to a
regimen of heparin and low dose aspirin, (1) reduces the rate of APOs in women with clinical APS and LAC,
and (2) alters angiogenic markers of poor placental vascularization. We will conduct an open label single
stage Phase II trial of certolizumab (a TNF-α inhibitor that does not cross the placenta). The potential public
health impact of this trial extends beyond the population of women with APS. A reduction of severe APOs in
certolizumab-treated patients would provide a rationale for trials of TNF-α blockade in pregnant women without
APS, but at risk for severe PE or PI, and extend the benefits of measuring angiogenic factor biomarkers in
early pregnancy to many more patients.

## Key facts

- **NIH application ID:** 10175669
- **Project number:** 3R21AR069189-03S1
- **Recipient organization:** HOSPITAL FOR SPECIAL SURGERY
- **Principal Investigator:** D.Ware Branch
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $196,279
- **Award type:** 3
- **Project period:** 2016-08-15 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10175669

## Citation

> US National Institutes of Health, RePORTER application 10175669, TNF-alpha Blockade with Certolizumab to Prevent Pregnancy Complications in High-Risk Patients with APS (3R21AR069189-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10175669. Licensed CC0.

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