Preeclampsia: What’s New in Prediction and Prevention?

6/14/19 AIM Conference, San Francisco

Roxanna A. Irani, MD, PhDAssistant ProfessorMedical Director, Outpatient Obstetrics Mission Bay

Preeclampsia: What’s new in prediction and prevention?2

Disclosures

Financial: None.

Academically: I’m a biochemistry nerd.

Preeclampsia: What’s new in prediction and prevention?3

Outline

1) Definition of preeclampsia

2) Known predictors (≠ biomarkers)

3) Preventative measures currently used

4) Biological markers of PEC

5) What’s on the horizon

6) Clinical implications

Defining Preeclampsia (PEC = HDP)

Diagnosed clinically >20 weeks

Hypertension +/- proteinuria depending on severe features

Systemic disorder leading to end-organ damage

~5% of pregnancies

Etiology is multifactorial

Responsible for significant maternal and fetal morbidity- Worldwide: 14%- United States: 7.4%- Burden of prematurity

Creanga 2017; Say. 2014; www.cdc.gov/reproductivehealth/maternalinfanthealth

Why should we care?

Attention of the lay media…

Identifying maternal risk factors is not enough…

We need to better tools to predict and prevent

this condition

Preeclampsia: What’s new in prediction and prevention?6

Predictors of PEC: Maternal risk factorsWhat do we know?... How do we counsel?

Clinical predictors with low

PPV

Risk factor Mean RR (95% CI)

Antiphospholipid syndrome 9.72 (4.34–21.75)

Previous preeclampsia 7.19 (5.85–8.83)

Insulin-dependent diabetes 3.56 (2.54–4.99)

Multiple pregnancy 2.93 (2.04–4.21)

Nulliparity 2.91 (1.28–6.61)

Family history of preeclampsia 2.90 (1.70–4.93)

Obesity 2.47 (1.66–3.67)

Age >40 years 1.96 (1.34–2.87)

Preexisting hypertension 1.38 (1.01–1.87)

Low PAPP-A (

Preeclampsia: What’s new in prediction and prevention?9

Outline

1) Definition of preeclampsia

2) Known predictors

3) Preventative measures currently used

4) Biological markers of PEC

5) What’s on the horizon

6) Clinical implications

Preeclampsia: What’s new in prediction and prevention?10

Prevention of PEC: What do we do now?

Take a thorough history

Baseline labs

Aspirin (ASA, acetylsalicylic acid)

Educate patients

Close surveillance

Serial labs - only for symptoms and diagnosis of condition

Delivery timingNot as much as we’d like

Preeclampsia: What’s new in prediction and prevention?11

Aspirin

Only RFs from history alone

“High Risk” factors ~8% incidence of PEC

Screening PPV 8-33%; better for early onset

Preeclampsia: What’s new in prediction and prevention?12

Aspirin: Background Hippocrates used willow tree extracts to reduce fevers (400 BC)

Anti-inflammatory, anti-pyretic, analgesia

NSAID: Irreversible COX-1 and COX-2 inhibitor

Nobel Prize to Sir John Vane (1970)

Decreases prostaglandin synthesis

Irreversibly blocks formation of thromboxane A2 in platelets

Preeclampsia: What’s new in prediction and prevention?13

In Theory: How does ASA prevent PEC?

TXA2: potent platelet aggregator and vasoconstictor- Synthesized by endothelial cells, activated platelets & macrophages- Increased in women with PEC

Platelet function is blocked by ASA at doses ≥ 100mg

At doses ≤100mg, mainly PG synthesis is affected

14

Meta-analyses of RCTs have reported contradictory results - GA at the onset of treatment < or > 16 wga- Dosing < or > than 100mg

Roberge 2017: LDA has little effect on preventing Sev PEC/FGR

Meher 2016: Reduced PEC by 10%, and not effected by timing/dose

Roberge 2013: Only looked at LDA, but most effective

Preeclampsia: What’s new in prediction and prevention?18

ASA Meta-Anaylsis Results Overall Administration of ASA was associated with:

- Reducing the risk of PT PEC (RR, 0.62; 95% CI, 0.45-0.87), - No significant effect on Term PEC (RR, 0.92; 95% CI, 0.70-1.21).

Reduction in PT PEC was confined to the subgroup in which ASA - Was initiated at

Preeclampsia: What’s new in prediction and prevention?21

PEC: Inflammation and Vascular damageBiologic Markers of PEC

sFlt

sEng

Thromboxane A2

ET-1

TNF-α

IL-6

IL-8

AT1-AA

↓ PlGF ↓ Pregnancy-Associated Plasma Protein-A (PAPP-A)

We don’t exploit these known

molecules

… Can we?

22

sFlt-1 = soluble fms-like tyrosine kinase 1 = inhibits VEGF

sEng = soluble endoglin = inhibits TGF-β1

Made by syncytiotrophoblasts

Elevated in maternal serum prior to PEC diagnosis- Level varies with disease severity

Anti-Angiogenic Factors:

Preeclampsia: What’s new in prediction and prevention?

No one biochemical test reliably predicts preeclampsia & demonstrates prospective clinical utility no treatment yet.

Karumanchi, 2016; Bergmann 2010; Ahmad 2004; Levine NEJM 2004; Herraiz 2014

Injection into pregnant rats produces preeclampsia-like state

Elevated ratio of sFlt-1 or sEng over PlGF in 2nd TM associated with PEC

23

Inflammatory Factors:

TNF-α

IL-6

IL-8

AT1-AA- Angiotensin II receptor Type 1 Autoantibody- Activates RAS system- Non-pregnant: Rejected kidney transplants

Pregnancy-Associated Plasma Protein-A (PAPP-A)- Metalloprotease; collagen binding (placental function)- Regulates IGF (fetal development)- Non-pregnant: Acute coronary syndrome, atherosclerosis, ESRD

Preeclampsia: What’s new in prediction and prevention?

Etiology: Maternal immune response

Borzychowski 2005; Schiessl 2007; Redman 2005

Cytokine balance

Th2 Anti-inflammatory

IL-4, IL-10IL-13, TGF-β

Th1 Pro-inflammatory

IL-6, IL-8IFN-γ, TNF-α

Uncomplicated pregnancyPreeclampsia

Placental hypoxia/ischemia Pro-inflammatory state PEC

Redman 2004; Lau 2006; Irani 2010; Conrad 1988; LaMarca 2007; Saito 2011; Keelan 2007

• TNF-α is increased in the serum of PEC patients

• Contributes to endothelial damage

PEC and the placental hypoxic/ischemic states

Chakravarty, 2006; Ali, 2010

Seaburg, 2005; Balsari, 1986; Herrera, 2006

HYPERTENSION

INFLAMMATION

Animal Models Humans

Use of alloactivated T cells for cancer txt → induces HTN

HIV patients → low BP/NT On txt → induces HTN

Immunosuppressive thx in RA and psoriasis pts → lowers BP

TNF-α blockers in pts with: RAPsoriasisCAD with chronic HTN

→ lowers BP

Thymectomy in salt sensitive HTNsive rats → lowers BP

Rodriguez, 2002; Guzik, 2007

Suppression of T cell action in salt sensitive rats → lowers BP

TNF-α blockers in salt sensitive rats → lower BP

TNF-α

Hurlimann, 2002; Lipsky, 2000; Mutru, 1989; Fichtlscherer, 2001

TNF-α is increased in patients with RA, SLE and MS.When pregnant, they have a high incidence of PEC.

When on immunosuppressive treatment : Risk of PEC is decreased.

Elmarakby, 2006, 2008; Flesch, 2003; Branen, 2004; LaMarca 2008

Blockade of TNF-α in RUPP rats→ lowers BP

TNF-α/apoE deficient mice→ lower BP → reduced atherosclerosis

Treatment PEC: Potential role of Certolizumab pegol (CZP)

No drugs

No interventions

No cure

• TNF-α antagonists (e.g. infliximab, adalimumab) used ~safely in pregnancy

• CZP: Polyethylene-glycolylated Fab’ fragment of humanized anti-TNF-α monoclonal antibody

• Lacks the Fc portion

• Reduced entry into fetal circulation

DELIVERY (DELAYED)

Limited placental transport makes CZP a desirable therapeutic candidate for PEC

D’Haens 2011; Norgard 2007; Clowse ME 2015; Mahadevan 2015; www.cimzia.com

CZP may decrease known inflammatory & vascular mediators in PEC

↑ Immune mediators

IL-6IL-8

MCP-1

Systemic maternal signs and symptoms of preeclampsia

Release of placental factors into maternal circulation

↑ Vascular mediators

sFlt-1ET-1

↑ TNF-α action on endothelial cells

↑ Systemic TNF-α

Placental hypoxia

CZP

Maynard 2003; Kupferminc 1994; Vince 1995; Szarka 2010; Karumanchi 2004; Levine 2004

Current Clinical Trials with CZP

IMPACT Study: IMProve Pregnancy in APS with Certolizumab Therapy (Dr. Ware Branch; U of Utah, U of Toronto, NYU)

Pregnancies with APLAS (+LAC)

Primary outcomes: Fetal

Secondary outcomes: Preeclampsia or placental insufficiency

PEC clinical trials: Need FDA approval to administer >28 weeks

-ish

Ben-Horin 2010, 2011; Woller 2016Preeclampsia: What’s new in prediction and prevention?30

Clinical Implications

Early detection of high risk gravid women

+/- Serial labs to predict and trend

Intervene prior to EOD or placental/fetal effects

Offer treatment other than delivery; reduce PT burden

Thank you! Questions?

roxanna.irani@ucsf.edu