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

> **NIH NIH R21** · HOSPITAL FOR SPECIAL SURGERY · 2022 · $174,810

## 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 conducting
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 are enrolling pregnant women in 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:** 10670566
- **Project number:** 3R21AR069189-03S2
- **Recipient organization:** HOSPITAL FOR SPECIAL SURGERY
- **Principal Investigator:** D.Ware Branch
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $174,810
- **Award type:** 3
- **Project period:** 2016-08-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10670566

## Citation

> US National Institutes of Health, RePORTER application 10670566, TNF-alpha Blockade with Certolizumab to Prevent Pregnancy Complications in High-Risk Patients with APS (3R21AR069189-03S2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10670566. Licensed CC0.

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