Filtering a key protein from maternal blood may be a safe way to extend pregnancy in cases of very preterm preeclampsia, based on results of a first-in-human pilot study.

Selectively removing soluble Fms-like tyrosine kinase 1 (sFlt-1) — a central mediator of preeclampsia — from maternal blood was associated with modestly reduced maternal blood pressure and 10 days of additional pregnancy time, reported lead author Ravi Thadhani, MD, of Cedars-Sinai Medical Center, Los Angeles, and colleagues.

“[O]ur study provides the necessary groundwork to address one of the most devastating complications of pregnancy,” the investigators wrote in Nature Medicine.

Apheresis Used to Reduce sFlt-1 in Maternal Blood

Rather than administering a drug, Thadhani and colleagues pursued a subtractive approach: an apheresis device that filters sFlt-1 from maternal plasma using an anti-sFlt-1 monoclonal antibody column.

It was first tested in five healthy nonpregnant volunteers, who tolerated single 0.25-plasma-volume treatments without complement activation or antibody leaching.

Next, the investigators conducted a single-arm, open-label pilot trial involving 16 women with very preterm preeclampsia and elevated sFlt-1 levels. Median gestational age was 30.3 weeks.

In phase A, seven pregnant women received single ascending doses of 0.25-0.75 plasma volumes; further dose escalation was not pursued because longer treatments in the Fowlers position were poorly tolerated.

In phase B, nine women received 0.50 plasma volumes up to twice weekly until delivery or 34 weeks of gestation, with each treatment lasting a mean of 93 minutes. Each session lowered sFlt-1 by a mean of 16.7% and mean arterial pressure by 4.1 mm Hg, with the two changes strongly correlated (R = 0.63).

Pregnancies continued for a median of 10 days (range, 3-19) after admission. Compared with 16 contemporaneous untreated women who met study criteria but lacked apheresis access, the treated group had roughly twice the pregnancy extension.

Fetal growth remained stable across both phase A and B, with neonatal birth weights generally matching or exceeding antenatal estimates. The procedure was well tolerated; mild treatment-related adverse events were limited to three cases of transient hypocalcemia, one skin hemorrhage at an access site, and one episode of false labor.

Optimization and Real-World Implementation

This was a proof-of-concept study that showed feasibility and safety, Thadhani and senior author S. Ananth Karumanchi, MD, also of Cedars-Sinai Medical Center, told Medscape Medical News. “We will need some optimization of the clinical protocol before a controlled clinical trial.”

Identifying which patients are most likely to benefit remains another key question. “Daily rate of rise of sFlt-1 is likely a key factor in determining the response,” Thadhani and Karumanchi said. Future work may also include daily monitoring of sFlt-1 elevation, they added.

In untreated, very preterm preeclampsia, sFlt-1 rises by roughly 500 pg/mL/d, the investigators said. Successfully interrupting the placental feedback loop should slow that rise to 50-100 pg/mL daily. “If the sFlt-1 does not go up, we will know that we have interrupted the positive loop and the patient may not need additional treatments,” Thadhani and Karumanchi explained.

As for real-world deployment, they expect early access will be constrained. Thadhani and Karumanchi plan to increase plasma volume per session, possibly with back-to-back treatments, to push sFlt-1 clearance to 30%.

The treatment “would be initially limited to tertiary care centers where very preterm preeclampsia [cases] are managed due to availability of level 3 or higher NICU for the management of preterm babies,” Thadhani and Karumanchi said.

More broadly, the investigators said the trial supports sFlt-1 as a viable target for future drug development. “Our findings confirm that sFlt-1 is [a] viable therapeutic target in humans,” Thadhani and Karumanchi said. “Epidemiological studies, experimental studies and genetic studies also suggest that sFlt-1 is [a] therapeutic target.

Outside Expert Highlights Promise of New Strategy

Sarosh Rana, MD, MPH, professor of obstetrics and gynecology at the University of Nebraska Medical Center, Omaha, Nebraska, told Medscape Medical News that she was moved to tears reading the study because it finally offers a path for treating very preterm preeclampsia.

Future clinicians will likely look back at this research as a “strong proof of concept” for treating preeclampsia, Rana said in an interview.

She emphasized that the observed 10-day extension of pregnancy is meaningful for patients in this gestational window. An extension of even 5 days gives clinicians enough time to administer betamethasone, Rana said, and completing a steroid cycle before delivery has an independent and significant effect on improving neonatal survival.

Regarding the modest 4.1 mm Hg reduction in mean arterial blood pressure, Rana viewed the result positively. Because sFlt-1 is biologically necessary to maintain utero-placental circulation, she cautioned that lowering the protein or the blood pressure too much could potentially compromise blood flow to the fetus.

“I was just happy that the blood pressures were not going up,” Rana said, noting that uncontrolled, incrementally worsening hypertension is a primary driver of iatrogenic delivery in these patients.

She also noted that the correlated reductions in sFlt-1 and mean arterial pressure strongly support the hypothesis that sFlt-1 is a major driver of preeclampsia. This knowledge may accelerate the development of pharmaceutical interventions, including those designed to reduce placental sFlt-1 production.

Looking ahead, Rana envisions the apheresis strategy fitting into clinical practice at tertiary care centers, potentially in combination with emerging drug therapies. Because such agents may take days to reduce sFlt-1 production, patients could conceivably undergo apheresis while medication takes effect.

“Look at us,” she said. “We are obstetricians — we don’t really do many innovations. No new drugs come in our hands.” So, she said, “this is amazing, actually.”

The study was funded by Miltenyi Biomedicine and Aggamin Pharmaceuticals. The investigators disclosed relationships with Thermo Fisher Scientific, Aggamin Pharmaceuticals, Comanche Biopharma, and others. Rana disclosed receiving biomarker research funding from Thermo Fisher Scientific and Roche.