prevention of Preeclampsia: An evidence based approach, 2015

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prevention of Preeclampsia An evidence based
approach, 2015

• Prof Aboubakr Elnashar
• Benha University Hospital, Egypt

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CONTENTS

• Introduction
• Pathogenesis
• Types of Prevention
• Level of evidence
• Methods of prevention
• Pharmacological
• Diet and supplements
• Other
• Recommendation

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• INTRODUCTION
• PE
• Syndrome of new onset of Hypertension
• and either
• Proteinuria or
• End organ dysfunction
• after 20 w in a previously normotensive woman

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• Pathogenesis
• incompletely understood
• (Barton Sibai, 2008).
• Hallmarks
• Impaired remodeling of uterine spiral arteries
• placental perfusion
• trophoblast differentiation
  invasion
• Placental endothelial dysfunction
• Immune maladaptation to paternal Ags
• Exaggerated systemic inflam response.
• production of
  antiangiogenic factors

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In PE Impaired trophoblast differentiation
invasion
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Placental and endothelial dysfunction
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• Risk factors
• Hypertension
• Reduced renal function
• Obesity, insulin resistance, diabetes
• History of PE
• Maternal genetic or acquired thrombophilias

• Pathogenesis
• Differs with various risk factors
• PG Vs MG with previous PE
• preexisting vas dis
• preexisting DM or
• multifetal gestation.

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• Why prevention of PE?
• There are no validated methods (biomarkers,
  clinical diagnostic tests, medical history) for
  prediction of PE.
• Maternal and perinatal morbidity and mortality
• common
• The only effective treatment
• Early delivery preterm birth in many cases
• Prevention of PE significant impact on maternal
  and infant health

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TYPES OF PREVENTION

• Primary
• Avoiding occurrence of the disease
• Obese
• achieve an ideal b wt before conception
  (Villamor Cnattingius, 2006)
• No RCT
• Ch hypertension
• Control BP before conception.
• No RCT

• Pregestational DM
• -Complete her family as early as possible before
  vascular complications develop
• -Control DM before conception throughout
  pregnancy

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• Secondary
• Breaking off the disease process before emergence
  of obvious clinical disease
• Etiology of the disease is unknown
• To correct theoretical pathophysiology

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• Tertiary
• Prevent complications of the disease
• close follow up of high risk women
• early diagnosis of PE followed by appropriate
  management may prevent some of the dangerous
  sequelae of the disease, such as eclamptic
  seizures and multiorgan failure.

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METHODS OF PREVENTION

• PHARMACOLOGIC
• Low dose aspirin
• Heparin
• Anti hypertensive
• Diuretics
• Progestgen

II. DIET SUPPLEMENTS

• III. OTHER
• Bed Rest
• Life style changes
• Exercise
• Wt loss

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Cochrane Systematic Review Gold Standard' for
high-quality systematic reviews
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• I. PHARMACOLOGICAL
• 1. Low dose aspirin
• Rationale
• PE
• increased platelet turnover
• increased platelet derived thromboxane levels
• low dose aspirin
• diminishes platelet thromboxane A2 synthesis
  while maintaining vascular wall prostacyclin
  synthesis altering the balance in favor of
  prostacyclin

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• I. Studies on moderate and high risk women
• low dose aspirin effective
• modest reduction in risk of
• PE (0-3 in treated vs 12-35 in
  controls)
• other adverse pregnancy outcome
• PTL, IUGR (by 10-20).
• Dekker et al, 2001.level 2 evidence (Cochrane
  SR, 2007 )

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• When to start?
• 16 w
• significant reduction in
• PE
• (RR 0.47, 95 CI 0.360.62 7.6 vs 17.9)
• severe PE
• (RR 0.18, 95 CI 0.080.41 1.5 vs 12.3)
• IUGR (RR 0.46 8.0 vs 17.6)
• PTL
• (RR 0.35, 95 CI 0.220.57 4.8 vs 13.4)
• Roberge et al, 2013 Meher et al, 2013.

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• Rate of reduction
• PE
• (RR 0.76, 95 CI 0.620.95 9.5 vs 11.4)
• IUGR
• (RR 0.80, CI 0.650.99 7.7 vs 8.6)
• PTL
• (RR 0.86, CI 0.760.98 21.7 vs 24.4), but not
  perinatal mortality
• Henderson et al, 2014 United States Preventive
  Services Task Force (USPSTF) .
• Risk reductions of 10 for PE, IUGR, and PTL
• Absolute risk reductions for
• PE 2-5
• IUGR 1-5
• PTL 2-4

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• II. Unselected nulliparous women
• little or no benefit
• Sibai et al, 1993
• no effect on incidence of FGR, or length of
  gestation
• Subtil et al, 2003.
• 1. Although nulliparity is a risk factor for PE,
  prevalence rates are relatively low (4) compared
  with moderate to high risk groups (8-30)
• Henderson et al, 2014.
• 2. Pathogenesis of PE in nulliparous is different
  from that in women with previous PE or
  preexisting vascular disease
• Sibai et al, 2005.

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• III. Studies on women with abnormal uterine
  artery Doppler (UAD)
• Abnormal UAD identified women who are likely to
  develop PE and IUGR
• Subtil et al, 2003.
• PE 6 vs 1
• IUGR 18 vs 8
• low dose aspirin of abnormal UAD
• Did not reduce the incidence of PE
• PE occurred in 2 of patients in each group.
• Did not reduce the incidence of IUGR.

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• Limitations of this trial
• low dose aspirin started late (22 -25 w), after
  significant pathologic changes had already
  occurred in the uteroplacental vasculature
• low rate of PE may have precluded finding a
  significant reduction in disease.

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• low dose aspirin at or before 16 w reduced the
  risk of
• PE
• (RR 0.6, 95 CI 0.40.8)
• Severe PE
• (RR 0.3, 95 CI 0.10.7)
• Villa et al, 2013.
• Routine Doppler surveillance has not been proven.
  

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• Guidelines
• ACOG, 2013
• low dose aspirin
• not recommended for women at low risk for PE.
• Recommend in high risk women women with history
  of
• early onset PE
• superimposed PE plus delivery at lt34 w or
• PE in gt1 pregnancy.

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• Cochrane SR, 2000
• NNT
• For moderate and high risk women
• 59 to 167 to prevent one case of PE
• 44 to 200 to prevent one PTL
• 125 to over 10,000 to prevent one perinatal death
  

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• NICE, 2010
• low dose (75 mg) aspirin for
• 1 high risk factor for PE
• chronic hypertension
• kidney disease
• diabetes
• autoimmune disease
• hypertension in previous pregnancy OR
• 2 moderate risk factors for PE
• age 40 y
• first pregnancy
• multiple gestation
• gt10 y between pregnancies,
• BMI35 kg/m at presentation
• family history of PE

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• American College of Chest Physicians, 2012
• low dose aspirin
• starting from 2nd T and continuing throughout
  pregnancy in women considered to be at risk for
  PE.
• American Heart Association, 2014
• low dose aspirin from the 12th w until delivery
  women with
• chronic primary or secondary hypertension or
• previous pregnanc y related hypertension

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• US Preventive Services Task Force (USPSTF) 2014
• Low dose aspirin
• 1 high risk factors
• absolute risk for PE 8.
• No validated methods (biomarkers, clinical
  diagnostic tests, medical history) for
  identifying women at high risk for PE
• 81 mg/d
• at 12 w
• Discontinue
• 5 to 10 days before expected delivery
• diminish the risk of bleeding during delivery
• Hirsh et al, 2008

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• Management of worsening PE
• Low dose aspirin
• little or no benefit in women who already have
  developed PIH
• CLASP study, 1994.
• At this late stage
• aspirin does not prevent progression to more
  severe disease
• exacerbate a bleeding diathesis in patients with
  the HELLP syndrome.

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• 2. Heparin
• Rationale
• The preeclamptic placenta features of
  uteroplacental ischemia
• increased syncytial knots and intervillous fibrin
• distal villous hypoplasia,
• villous infarcts
• decidual necrosis
• spiral artery abnormalities including acute
  atherosis, mural hypertrophy, and luminal
  thrombosis/fibrous obliteration.

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• LMWH
• women with a history of early onset, severe PE
  reduce risk of recurrence
• lower quality evidence
• Mello et al, 2005.

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• Women with and without thrombophilia with
  previous late onset, non severe PE and previous
  mildly SFGA (B wt between 5th and 10th
  percentile) should not be offered LMWH to
  prevent recurrent placenta mediated pregnancy
  complications
• The best available evidence did not show a clear
  benefit
• Rodger et al, MA, 2014.
• LMWH is not recommended for reducing the risk of
  PE in either the general population or in those
  with PE in a previous pregnancy.

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• 3. Antihypertensive drugs
• Severe hypertension (D110 mmHg or S 160 mmHg)
• reduces the risk of stroke
• Moderate hypertension (D100 to 109 mmHg or S 150
  to 159 mmHg)
• reduce this risk.
• Mild to moderate hypertension
• Halving in the risk of developing severe
  hypertension
• No difference in the risk of developing PE or
  proteinuria
• (Cochrane SR, 2007)

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• lowering BP
• Not reduce the risk of PE or abruption
• Not improve fetal or pregnancy outcome
• Not decrease incidence of moderate and severe
  hypertension.
• (Cochrane SR 2007)

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• 4. Diuretics
• No reduction in the incidence of PE or perinatal
  mortality
• May have deleterious effects
• reduced renal placental perfusion.
• (Cochrane SR, 2007 )

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• 5. Progesterone
• Insufficient evidence for preventing PE
• (Cochrane SR 2006)
• progesterone should not be used for this purpose
  in clinical practice at present.

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II. DIET AND SUPPLEMENTS

• Vit
• C and or E
• D
• Folic acid
• B2
• B6

• Minerals
• Calcium
• Mg
• Zn

• Fish oil
• Nitric acid donors
• Antioxidants

• Garlic
• Salt restriction
• Pr and energy restriction
• Vegetables, fruits, and vegetable oils

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• Minerals
• Calcium supplementation
• RDA for elemental calcium in USA
• 1000 mg/d in pregnant and lactating women 19 to
  50 y of age (1300 mg for girls 14 to 18 y) this
  is the same for lactating and nonlactating women
  of the same age.

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• Calcium supplementation ( 1 g/d)
• significant reduction in
• PE particularly for women with low calcium diets.
  
• (Cochrane SR, 214)
• PTL

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• Calcium supplementation (1 g/d)
• halved the risk of
• PE
• (RR 0.45, 95 CI 0.310.65)
• hypertension
• (RR 0.65, 95 CI 0.530.81).
• The reduction in risk ratio was greatest for
• women at high risk of PE
• (RR 0.22, 95 CI 0.120.42),
• those with low baseline calcium intake
• (RR 0.36, 95 CI 0.200.65).
• low risk women with adequate dietary
• calcium intake no benefit
• Hofmeyr et al, 2014.

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• WHO Guidelines 2011
• 1.52.0 g elemental calcium/d for pregnant women
  in areas with low dietary calcium.

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• Calcium supplementation lt1 g daily
• Significant reduction in risk of PE
• but the trials were small and most had a high
  risk of bias or other methodological limitations
• (Hofmeyr et al, 2014)
• In settings of low dietary calcium where
  high-dose supplementation is not feasible
  lower-dose supplements (500 to 600 mg/d) might be
  considered in preference to no supplementation.
• (Cochrane SR, 214)

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• 2. Magnesium
• Rationale
• Mg is beneficial for the prevention tt of severe
  PE E
• Decreased intracellular Mg in PE
• 365 mg 500 mg
• No effect
• (Cochrane SR, 2004 )
• 3. Zinc
• Zinc concentrations are reduced in PE
• RCT No benefit
• (Jonsson et al, 1996)

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• Vitamins
• C and/ or E
• Rationale
• PET imbalance of oxidant antioxidant activity
  multi organ endothelial dysfunction

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• Vit C (1,000 mg/d) and/ or vit E (400 IU/ d) for
  high risk for PE
• No prevention
• slightly increased
• gestational hypertension (RR 1.11, 95 CI
  1.051.17)
• LBW infants (RR 1.73, 95 CI)
• McCance et al, 2010 CondeAgudelo et al, 2011
• Not recommend for prevention or tt of PE.
• level 2 evidence
• (Cochrane SR, 2015)

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• 2. Vitamin D supplements
• Rationale
• Vit D deficiency increased risk of PE
• Bodnar et al, 2007 Robinson et al, 2010,
  observation study
• Vit D supplementation (10 to 15 microg/d 400 to
  600 IU/d)
• 29 reduction of PE
• Haugen et al, observation study,2009 Hyppönen
  et al, 2014)
• No association
• Shand et al, Prospective Cohort study. 2010,
• The quality of evidence is insufficient
• (Hyppönen et al, MA, 2014)
• Pregnant women who do not have regular effective
  sun exposure should consume 600 IU of vit D
  daily.

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• 3. Folic acid
• Controversial
• Wen eta l, 2013.
• Regardless, periconceptional folic acid
  supplementation is recommended to
• reduce NTD
• 4. Vit B2
• Deficiency of vit B2 may cause biochemical
  changes simulating abnormalities of PE
• No evidence
• (Shrama Mittal, 2006).
• 5. Vit B6
• No enough evidence
• (Cochrane SR, 2015)

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• 1. Fish oil
• Observational studies beneficial effects
• (Sørensen et al, 1993)
• inhibition of platelet thromboxane A2 without
  affecting prostacyclin shifting the balance
  toward a reduced platelet aggregation and
  increased VD.
• RCT No benefit
• (Olsen et al, 2000 Olsen et al, 2000 Villar et
  al, 2004, RCT, Cochrane SR, 2006.
• High doses increase the risk of PIH
• (Olafasdottir et al, 2006).
• Not recommended for the prevention of PE

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• 2. Nitric oxide donors
• Rationale
• Preeclamptic women may be deficient in nitric
  oxide, which mediates VD and inhibits platelet
  aggregation
• Nitric oxide donors glyceryl trinitrate
• did not prevent PE
• (Cochrane SR, 2007).

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• L arginine
• Substrate for synthesis of nitric oxide.
• Reduction in 
• PE
• (RR 0.34, 95 CI 0.21-0.55)
• PTL
• (RR 0.48 and 95 CI 0.28 to 0.81).
• (Dorniak-Wall et al, MA, 2014)

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• 3. Antioxidants
• Rationale
• PE has been described as a two stage process
• reduced placental perfusion followed by
• release of placental factors trigger maternal
  endothelial cell dysfunction
• Roberts et al, 1999.
• Oxidative stress endothelial cell dysfunction.
• Evidence does not support routine antioxidant
  supplementation to reduce the risk of PE
• level 2 evidence
• (Cochrane Library 2008 )

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• Diet
• 1. Garlic
• Insufficient evidence
• to recommend for
• preventing PE
• (Cochrane Library 2006 )
• 2. Dietary sodium restriction
• No significant differences
• (Cochrane Library 2005 )
• salt consumption during pregnancy should remain a
  matter of personal preference.

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3. Protein and energy restriction (in obese
women) Cochrane SR, 2005. 4. High intake of
vegetables, fruits, and vegetable
oils Brantsaeter et al, 2009.
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III. OTHER

• 1.Daily Bed rest
• Rest (4-6 h/d) for women with normal BP
• reduce risk of
• PE
• (level 2 evidence)
• (Cochrane Library 2006 )
• reflect bias and/or random error rather than a
  true effect.
• Current evidence is insufficient
• to support recommending rest or reduced activity
  to women for preventing PE and its complications.
  Whether women rest during pregnancy should
  therefore be a matter of personal choice.

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• Rest for women with hypertension during pregnancy
• one small trial reduced risk of
  severe hypertension and PTL
• Need to be confirmed in larger trials.
• Insufficient evidence to provide clear guidance
  for clinical practice bed rest should not be
  recommended routinely for hypertension in
  pregnancy
• (Cochrane SR, 2005)

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• 2. Life-style changes
• High job stress greater risk of PE
• (Sharma Mittal, 2006)
• Reducing job stress may be beneficial in the
  prevention of PE
•  

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• 3. Regular prenatal exercise
• Rationale
• (Weissgerber et al, 2004)
• Stimulation of placental growth
• Reduction of oxidative stress
• Reversal of maternal endothelial dysfunction
• Aerobic exercise cardiovascular exerciseany
  sustained rhythmic activity that involves large
  muscle groups makes the lungs work harder as the
  body's need for oxygen is increased.

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• Aerobic exercise (of regular Moderate intensity)
• Insufficient evidence
• (Cochrane Library 2006)
• Stretching exercises
• more effective at reducing the risk of PE than
  walking
• (University of North Carolina,2008)
• protective effect
• (OR 6.34, 95 CI 0.7255.37,p 0.09).
• Insufficient evidence
• Kasawara et al, SR, 2012.

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• 4. Weight loss
• Rationale
• Maternal obesity
• an increased risk of PE
• Bariatric surgery
• significantly reduces the risk of PE
• Maggard SR, 2008.
• In women with PE
• weight loss between pregnancies reduced the risk
  of recurrent PE
• Mostello et al, 2010.

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• Smoking
• Reduced risk for PE
• (Sibai et al, 2005).
• Nicotine inhibition of interleukin-2 tumor
  necrosis factor
• Effects of nicotine on angiogenic proteins.
• abnormal fetal growth
• preterm birth
• Abruption
• Adverse effects on maternal health.

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• RECOMMENDATIONS
• Prevention of PE is important
• Low dose aspirin
• Recommended for women at moderate to high risk of
  developing PE
• (Grade 2B).
• Not recommended for women at low risk
• (Grade 1A).

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• A modest reduction in the risk of PE, IUGR and
  PTL
• 81 mg/d is recommended
• (Grade 2B),
• beginning at the end of 1st T.
• discontinued 5 to 10 days before expected
  delivery

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• Routine calcium supplementation
• above the recommended daily allowance (1000 mg/d)
  for healthy, nulliparous women is not recommended
  to prevent PE
• (Grade 1A).
• There may be a benefit for PE prevention in high
  risk populations or in those consuming a low
  calcium diet.

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• Vit C and E supplementation is not recommended to
  prevent PE
• (Grade 1A)
• Fish oil is not recommended for preventing PE
• (Grade 1A).

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