can we prevent preeclampsia? · preeclampsia risk factors from the reproductive care program of...

Can we prevent preeclAmpSiA?

The role of Ca2+ and early low-dose ASA

Choosing Wisely With Academic Detailing - October 27th, 2019

Michelle ten Brinke, BSc. Pharm ACPRPharmacistDrug Evaluation UnitNova Scotia Health Authority

Dr. Edith Baxter, MD CCFPFamily PhysicianDirector Evidence-based Programs in Continuing Professional Development Dalhousie University

Conflicts of InterestMichelle ten Brinke

◦ Grants:

◦ Canadian Society of Hospital Pharmacists (CSHP) Grant

◦ No other conflicts of interest to disclose

Dr. Edith Baxter

◦ No conflicts of interest to disclose

Learning Objectives1. To review the evidence for calcium supplementation during pregnancy to prevent

preeclampsia.

2. To review the evidence for low-dose ASA in high-risk pregnant women to prevent preeclampsia.*

3. Through a case, identify the characteristics of pregnant women for whom low-dose ASA should be considered.

* Note: Off-label use

Case

Amanda

Visit 1

• 34 year old

• Recent positive home pregnancy test

• Had been amenorrheic on OCP, then decided to dc

• Unable to reliably determine LMP

• Did not take prenatal folic acid, not currently on PN vit

• Two previous pregnancies:

• Last was 10 years ago

• Current medication: sertraline 100 mg

Case

Amanda

Visit 1

Calcium supplementation during pregnancy to prevent

preeclampsiaEvidence Review and Recommendations

The Evidence

Hofmeyr GJ, Lawrie TA, Atallah AN, et al. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 2018,10:CD001059.

2018 Cochrane Review27 Trials (N = 18,064)

◦ High dose calcium supplementation (≥ 1 g elemental calcium/day) vs. placebo

◦ n = 15,730

◦ Low dose calcium supplementation (< 1 g elemental calcium/day) vs. placebo/no treatment

◦ n = 2334

◦ High dose vs. low dose calcium supplementation

◦ n = 262


2018 Cochrane ReviewPrimary Outcomes:

◦ Women

◦ High blood pressure (with or without proteinuria)

◦ Preeclampsia

◦ Children

◦ Preterm birth

◦ Admission to NICU

◦ Stillbirth or death before discharge from hospital

Subgroup Analysis:

◦ Calcium Intake

◦ Low vs. adequate baseline dietary calcium intake

◦ Risk

◦ Low / average risk vs. high risk of hypertensive disorders of pregnancy


High‐dose Calcium Supplementation vs. PlaceboPre‐eclampsia


2018 Cochrane ReviewHigh dose calcium supplementation also decreases the risk of:

◦ Hypertension

◦ RR = 0.65; 95% CI 0.53-0.81

◦ Preterm birth in those at high risk

◦ RR = 0.45; 95% CI 0.24-0.83

◦ Maternal death or serious morbidity in those with low calcium intake

◦ RR = 0.80; 95% CI 0.66-0.98

But… increases the risk of HELLP syndrome◦ 0.2% vs. 0.1%

◦ RR = 2.67; 95% CI 1.05-6.82

◦ Clinical significance?


Recommendations:The SOGC 2014 Guidelines on Diagnosis, Evaluation, and Management of the Hypertensive Disorders of Pregnancy:1

The Reproductive Care Program of Nova Scotia Recommends:2

Calcium supplementation with ≥ 1 g of elemental calcium/day in those with low calcium intake to prevent preeclampsia.

Recommendation GradeCalcium supplementation (of at least 1 g/day, orally) is recommended for women with low dietary intake of calcium (<600 mg/day), for preventing preeclampsia and its complications. Comments: An alternative to supplementation may be 3–4 dairy

servings/day (250–300 mg calcium/serving).

I-A; High/Strong

1) Magee LA, Pels A, Helewa M, et al. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. Pregnancy Hypertens 2014;4(2):105-45.doi :https://doi.org/10.1016/j.preghy.2014.01.003. This article is published under the terms of the Creative Commons Attribution-NonCommercial-No Derivatives License (CC BY NC ND) https://creativecommons.org/licenses/by-nc-nd/4.0/ .2) Personal Communication: Dr. Heather Scott, Obstetrical Medical Advisor Reproductive Care Program of Nova Scotia and Maternal Fetal Medicine Specialist, Department of Obstetrics & Gynaecology, Faculty of Medicine, Dalhousie University.

Calcium TipsMost prenatal multivitamins contain a limited amount of calcium.

Calcium salts (except calcium citrate) should be taken with food.

Doses of elemental calcium >500 mg/day should be administered in divided doses.

The administration time of calcium supplements or calcium rich foods should be spaced apart from some medications or supplements (e.g., iron or levothyroxine).

Encourage patients to speak to their pharmacist regarding appropriatetiming of calcium supplementation or dietary calcium consumption.

Calcium Salts: Oral product/CPhA monograph, 2014. In: Compendium of pharmaceuticals and specialties, online version (e-CPS). Canadian Pharmacists Association. Cited 2019 Mar 11. Available from: https://www.e-therapeutics.ca Nestle Baby. Nestle Materna Prenatal Multivitamin Product Information. Cited 2019 May 2. Available from: https://www.nestlebaby.ca/en/nestle-materna

https://www.nestlebaby.ca/en/nestle-materna

Low-dose ASA in high-risk pregnant women to prevent

preeclampsiaEvidence Review and Recommendations

Roberge et al. Meta-Analysis (2018)

Purpose:

◦ To determine the effect of ASA on preventing preterm and term preeclampsia

◦ To assess the impact of gestational age at onset of ASA therapy and dose

Roberge S, Bujold E, Nicolaides KH. Aspirin for the prevention of preterm and term preeclampsia: systematic review and meta-analysis. Am J Obstet Gynecol 2018;218(3):287-93.

Roberge et al. Meta-Analysis (2018)ASA vs. Placebo / No Treatment

◦ 16 RCTs (N = 18,907)


Roberge et al. Meta-Analysis (2018)


ASPRE Trial

Rolnik DL, Wright D, Poon LC, et al. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. N Engl J Med 2017; 377(7):613-22.

ASPRE Trial

Age ≥ 18 yearsSingleton pregnancy

High risk for preterm preeclampsia (https://fetalmedicine.org/research/asses

s/preeclampsia/first-trimester)

Exclusions included:• Taking ASA regularly

within 28 days before screening

• Bleeding disorders (e.g., von Willebrand’sdisease)

• Peptic ulceration• Long term NSAID use

Excluded those with a high bleed risk

Intervention & ControlPatient Population

ASA 150 mg or Placebo

Once Daily @

Starting at 11-14 weeks gestation & continued until 36 weeks gestation


https://fetalmedicine.org/research/assess/preeclampsia/first-trimester

The Fetal Medicine Foundation. Risk for preeclampsia (11+0 to 14+1 weeks gestation). Available at: https://fetalmedicine.org/research/assess/preeclampsia/first-trimester

ASPRE TrialPrimary Outcome:

◦ Preterm Preeclampsia

Secondary Outcomes:◦ Adverse outcomes of pregnancy

◦ Stillbirth or neonatal death

◦ Neonatal death and complications

◦ Neonatal therapy

◦ Poor fetal growth

Results:

26,941 women were screened

Only 2641 met eligibility criteria

1776 enrolled


ASPRE TrialAdverse Events (AE):

ASA(N = 798)

Placebo(N = 822)

p value

At least one AE 25.9% 25.5% NS

At least one serious AE 1.6% 3.1% Not reported

Nausea and/or vomiting 5.0% 4.4% NS

Abdominal and/or pelvic pain 3.3% 4.0% NS

Dyspepsia and/or heartburn 2.4% 2.7% NS

Vaginal bleeding 3.6% 2.6% NS

Anemia 0.5% 0.9% NS


Knowledge Translation of ASPREASA 150mg vs. Placebo to Prevent Preterm Preeclampsia:

Dalhousie Knowledge Translation Clinical Significance Calculator. Available at: http://ktcalc.cme.dal.ca/site/login.phpCates Plot images have been produced using Dr Chris Cates’ software, Visual Rx version 4. Available at: https://www.nntonline.net/visualrx/

http://ktcalc.cme.dal.ca/site/login.php

https://www.nntonline.net/visualrx/

Recommendations:The Reproductive Care Program of Nova Scotia Recommends:

In pregnant women at high risk for developing pre-eclampsia, initiating ASA 150 mg (or in its absence, 2 x 81 mg tablets = 162 mg) once daily at bedtime reduces the risk of preeclampsia. ASA should be:

• initiated between 11-16 weeks gestation (ideally between 11-14 weeks), and

• continued until 36 weeks gestation.

Personal Communication: Dr. Heather Scott, Obstetrical Medical Advisor Reproductive Care Program of Nova Scotia and Maternal Fetal Medicine Specialist, Department of Obstetrics & Gynaecology, Faculty of Medicine, Dalhousie University.

Preeclampsia Risk FactorsFrom the Reproductive Care Program of Nova Scotia:

Patients at high risk of developing preeclampsia are those with one or more “high risk” factors. Patients with a combination of at least two “moderate risk” factors may also be identified at high risk for developing preeclampsia.

High Risk Factors Moderate Risk Factors• History of preeclampsia especially with an adverse

outcome• Multifetal gestation• Chronic hypertension• Type 1 or 2 diabetes mellitus • Renal disease• Autoimmune disease (antiphospholipid syndrome,

systemic lupus erythematosus)

• Nulliparity• Obesity (BMI >30)• Family history of preeclampsia in mother or sister• Age ≥ 40 years• African Canadian• Low socioeconomic status• History of:

• maternal low birth weight or small for gestational age,• previous adverse pregnancy outcome, or• greater than 10 year pregnancy interval.

Personal Communication: Dr. Heather Scott, Obstetrical Medical Advisor Reproductive Care Program of Nova Scotia and Maternal Fetal Medicine Specialist, Department of Obstetrics & Gynaecology, Faculty of Medicine, Dalhousie University.

Recommendations:2019 NICE Hypertension in Pregnancy: Diagnosis and Management Guidelines

National Institute for Health and Care Excellence. Hypertension in Pregnancy: Diagnosis and Management. 2019 NICE Guideline 133. Cited 2019 Sept 16. Available at: https://www.nice.org.uk/guidance/ng133/resources/hypertension-in-pregnancy-diagnosis-and-management-pdf-66141717671365

Recommendation 1.1.2:Advise pregnant women at high risk of pre-eclampsia to take 75–150 mg of aspirin daily from 12 weeks until the birth of the baby.

Recommendation 1.1.3:Advise pregnant women with more than 1 moderate risk factor for pre-eclampsia to take 75–150 mg of aspirin daily from 12 weeks until the birth of the baby.

Women at high risk are those with any of the following:

• Hypertensive disease during a previous pregnancy

• Chronic kidney disease• Autoimmune disease such as systemic lupus

erythematosus or antiphospholipid syndrome• Type 1 or type 2 diabetes• Chronic hypertension

Factors indicating moderate risk are:

• First pregnancy• Age ≥40 years• Pregnancy interval of more than 10 years• Body mass index of ≥35 kg/m2 at first visit• Family history of pre-eclampsia• Multi-fetal pregnancy

Back to the Case

Amanda

Visit 1

• 34 year old

• Recent positive home pregnancy test

• Had been amenorrheic on OCP, then decided to dc

• Unable to reliably determine LMP

• Did not take prenatal folic acid, not currently on PN vit

• Two previous pregnancies:

• Last was 10 years ago

• Current medication: sertraline 100 mg

Back to the Case

Amanda

Visit 1

Back to the Case

Amanda

Visit 2

• Review U/S: single intrauterine gestation, crown-rump length corresponds to gestational age of 12 weeks, 3 days

• BP on this visit is 140/95 mmHg

Back to the Case

Amanda

Visit 2

• How do you assess her risk of preeclampsia?

• Is there any additional information you would like to know in order to assess her risk?

• What interventions could be done at this visit to reduce her risk of developing preeclampsia?

The Fetal Medicine Foundation. Risk for preeclampsia (11+0 to 14+1 weeks gestation). Available at: https://fetalmedicine.org/research/assess/preeclampsia/first-trimester

We CAn prevent preeclAmpSiA!

Questions?

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