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Challenging clinical scenarios in hypertension.

Hypertension in pregnancy
Claudio Borghi, F.E.S.C., F.A.H.A,
Department of Medical and Surgical Sciences
University of Bologna
Bologna, Italy
Hypertension in pregnancy
Epidemiology

• Most common medical disorder in pregnancy


• On average it complicates 6-8% of all pregnancies (up to 15%)*
• Its prevalence is progressively increasing (age, other RF’s)*
• Responsible for the 12.3% of all pregnancy-related maternal deaths**
• Responsible for an increase in maternal/perinatal mortality and
morbidity* (mainly related to PE) and for an increase in the rate of
maternal CVD later in life***

* From Task Force of hypertension in pregnancy-ACOG, Ostet Gynecol 2013


** From Berg Cj et al, Obstet Gynecol 2010
*** From Mannisto T et al, Circulation 2013
Pre-eclampsia and risk of fatal and non-fatal ischaemic heart disease events in later life.

Bellamy L et al. BMJ 2007;335:974


Pre-eclampsia and risk of fatal and non-fatal stroke and thromboembolism in later life.

Bellamy L et al. BMJ 2007;335:974


The survival curves for total cardiovascular disease, myocardial infarcts, and myocardial infarct
deaths among women with hypertension during pregnancy.

Männistö T et al. Circulation. 2013;127:681-690


Pre-eclampsia and long-term adverse outcomes
in the offsprings: supporting evidence

• Children/adolescents exposed to PE have higher SBP and DBP

• The risk for stroke was twice than controls in subjects born
from pre-eclamptic pregnancies

1. The same observations have been confirmed in animal models


of pre-eclampsia

1. Studies performed in brothers exposed or not to preclamptic


pregnancies suggest an impaired vessel function associated to
preeclampsia per se.
ESH Guidelines, Eur Heart J 2011
Classification of HTN in pregnancy
American College of Obstetricians and Gynecologists

• Gestational Hypertension
• Chronic Hypertension (of any cause)
• Pre-eclampsia/eclampsia
• Chronic hypertension with superimposed pre-eclampsia

From ACOG. Task Force on HBP in Pregnancy, Obstetri Gynecol 2013; 122(5), 11221131
Classification of the Hypertensive Disorders
of Pregnancy by SOGC

Magee LA et Al. Diagnosis, Evaluation and management of Hypertensive Disorders of Pregnancy. JOCG, 2014
Hypertension in
pregnancy
An “heterogeneous”
hemodynamic and neurohumoral
disease
Frida Khalo, 1939
Defintion of pre-eclampsia
The management of HTN in pregnancy

• Should we reduce blood pressure ?


The reasons for the use of antihypertensive
drugs in pregnancy

• To prevent and treat severe hypertension


• To prolong pregnancy and maximize gestational age
• To minimize the fetal exposure to medications
• To improve long-term CV morbidity/mortality (?)
Comparison between different levels of BP control in
patients with non-proteinuric HTN in pregnancy *.
The CHIPS Randomized Controlled Trial

* 74-6% with pre existing HTN, 45.4% with gestational hypertension


Outcome Less tight BP control Tight BP control OR (95% CI)
(DBP<100 mmHG) (DBP<85 mmHg)
(n.497) (n.490)

Primary outcome 31.4% 30.7% 1.03 (0.78-1.36)

Secondary outcome 3.7% 2.0% 1.74 (0.79-3.84)

Rate of severe HTN (>160/110 mmHg) 40.4% 27.5% 1.78 (1.35-2.36)

• Primary (perinatal) outcome=Pregnancy loss or high neonatal care for the first 28 days of life
• Secondary (maternal) outcome=one/more serious maternal complications < 6 weeks

Magee LA et al, Arch Dis Child Neonatal Ed 2014; 99(suppl.1) A5-A6


(downloaded from fn. BMJ.com)
The management of HTN in pregnancy

• Should we reduce blood pressure ?


1. Which one is the goal of treatment ?
The goals of treating HTN during pregnancy are
the same among the different guidelines :

- prevention of maternal stroke


- prevention of other CV complications
- prevention of maternal target organ damage
- fetal protection
The management of HTN in pregnancy

• Should we reduce blood pressure ?


1. Which one is the goal of treatment ?
2. Who should be treated ?
CWG Redman BMJ 2011
Reasons not supporting the antihypertensive
treatment in mild-moderate HBP in pregnancy.

Non significant maternal benefit (±)


- young age of most patients
- brief duration of hypertension

Increased fetal risk


- impaired utero-placental perfusion
- exposure to medication with potential AE’s
The management of HTN in pregnancy

• Should we reduce blood pressure ?


1. Which one is the goal of treatment ?
2. Who should be treated ?
3. What antihypertensive drugs (oral treatment)?
Criteria for the choice of
antihypertensive drugs in pregnancy
The choice of antihypertensive drugs for the treatment of
hypertension in pregnancy is limited to those drugs that:

-Have long been in clinical use


-Have been proven to be effective in BP control
-Have been relatively well tolerated
-Have side-effects profile considered tolerable by obstetricians
First-line drugs for the oral treatment of hypertension
during pregnancy*

*Endorsed by: ESC Guidelines-2011, ESH-ESC Guidelines -2013, NICE Guidelines-2011, ACOG Guidelines-2013, SOCG
Guidelines-2014, ASH/FDA Guidelines 2008, Sibai BM, Obstet Gynecol 2003 , Podymow T, Hypertension 2008
Effects of nifedipine GITS and methyldopa on LV structure, function and
plasma levels of natriuretic peptides in 37 patients with preeclampsia

Atrial
P<0.01 Natriuretic
LVEF P<0.01
Peptide

LVESV
P<0.05

Brain
P<0.01 Natriuretic
P<0.01 Peptide
LVEDV

Borghi C et al J Hypertens 2004


On-going trials in Hypertension in pregnancy
Trial Topic Treatment Release
Gynuity Health Project HBP in pregnancy (severe) Methyldopa vs.labetalol vs. Niifedipine 2015
CHIPS HBP in pregnancy (GH-no proteinuria) Less tight vs.tight BP control 2014
GTPWHDP High-risk HBP in pregnancy Nifedipine vs. Labetalol 2013
CLONCAP HBP after pregnancy (post-PE) Captopril vs. clonidine 2013
No acronym HBP in pregnancy (Chronic) Oral L-Arginine vs. placebo 2009 (?)
4P Prevention of HTN in pregnancy Combined ASA and multinutrients 2016
Hydralazine Versus Hypertensive crisis Labetalol vs. Hydralazine 2013 (?)
Labetalol for the
Management of
Hypertensive Disorders
of Pregnancy

From: ClinicalTrials.gov
The management of HTN in pregnancy

• Should we reduce blood pressure ?


1. Which one is the goal of treatment ?
2. Who should be treated ?
3. What antihypertensive drugs (oral treatment)?
4. What are the perspectives for the future?
Therapeutic approaches to treating HTN in pregnancy

• Potential new targets for the treatment of PE:

Adenosine, L-arginine and NO (ALANO) pathway


Heme oxygenase-1 pathway
Endothelin-1 pathway
Recombinant angiogenic factors
AT1 receptor agonistic autoantibodies
Drugs with anti-inflammatory actions
Genetic approaches
L-carnitine?

Mod. from Mate A et Al, Drug Discovery Today 2012


Conclusions
• Hypertensive disorders in pregnancy (HDP) are a
major health issue for women and infants.
• The prevalence of HDP is increasing over time for
several different reasons.
• Pre-eclampsia either alone or superimposed to chronic HTN is the most
complicated disease and presents the major risks.
• According to Guidelines the management of HDP includes: the prevention of
the disease, an early diagnosis, an appropriate treatment during pregnancy
and an extensive follow-up program for mothers (and probably babies) to
reduce CV morbidity/mortality and to prevent CV disease later in life.
• Accordingly, women with HDP and in particular those with PE should be
considered eligible as a new target for primary CV prevention at earlier age.