This document discusses approaches to preventing preeclampsia. It begins by defining preeclampsia and outlining its pathogenesis. It then describes different types and levels of prevention evidence before examining various methods of prevention, including pharmacological interventions like low-dose aspirin, dietary supplements like calcium, and lifestyle changes. While some methods like low-dose aspirin for high-risk women and calcium supplementation are supported, evidence for other interventions is limited or they provide little benefit in preventing preeclampsia.

1. PREVENTION OF
PREECLAMPSIA:
An evidence based approach, 2015
Prof Aboubakr Elnashar
Benha University Hospital, Egypt
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2. CONTENTS
Introduction
 Pathogenesis
 Types of Prevention
 Level of evidence
Methods of prevention
 Pharmacological
 Diet and supplements
 Other
Recommendation
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3. 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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4. 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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5. In PE:
Impaired trophoblast
differentiation& invasion
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6. Placental and endothelial
dysfunction
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7. 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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8. 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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9. 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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10. 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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11. 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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12. METHODS OF PREVENTION
I. PHARMACOLOGIC
1. Low dose aspirin
2. Heparin
3. Anti hypertensive
4. Diuretics
5. Progestgen
II. DIET &
SUPPLEMENTS
III. OTHER
1. Bed Rest
2. Life style
changes
3. Exercise
4. Wt loss
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13. Cochrane Systematic Review
Gold Standard' for high-
quality systematic reviews AboubakrElnashar

14. 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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15. 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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16.  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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17. 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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18. 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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19. 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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20. Limitations of this trial:
1. low dose aspirin started late (22 -25 w), after
significant pathologic changes had already
occurred in the uteroplacental vasculature
2. low rate of PE may have precluded finding a
significant reduction in disease.
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21.  low dose aspirin at or before 16 w: reduced the
risk of
 PE
(RR 0.6, 95% CI 0.4–0.8)
 Severe PE
(RR 0.3, 95% CI 0.1–0.7)
[Villa et al, 2013].
 Routine Doppler surveillance has not been
proven.
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22. 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 <34 w or
PE in >1 pregnancy.
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23. 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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24. 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
>10 y between pregnancies,
BMI≥35 kg/m at presentation
family history of PE
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25. 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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26. 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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27. 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
1. aspirin does not prevent progression to more
severe disease
2. ±exacerbate a bleeding diathesis in patients with
the HELLP syndrome}.
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28. 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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29. 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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30. 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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31. 3. Antihypertensive drugs
Severe hypertension (D≥110 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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32. 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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33. 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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34. 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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35. II. DIET AND SUPPLEMENTS
Minerals:
 Calcium
 Mg
 Zn
Vit:
 C and or E
 D
 Folic acid
 B2
 B6
 Garlic
 Salt restriction
 Pr and energy
restriction
 Vegetables, fruits,
and vegetable oils
 Fish oil
 Nitric acid donors
 Antioxidants
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36. Minerals
1. 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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37. Calcium supplementation (≥ 1 g/d):
significant reduction in
PE particularly for women with low calcium diets.
(Cochrane SR, 214)
PTL
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38. 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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39. WHO Guidelines 2011
1.5–2.0 g elemental calcium/d for pregnant
women in areas with low dietary calcium.
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40. Calcium supplementation <1 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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41. 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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42. Vitamins
1. C and/ or E
Rationale:
PET: imbalance of oxidant & antioxidant activity:
multi organ endothelial dysfunction
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43. 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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44. 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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45. 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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46. 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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47. 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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48. 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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49. 3. Antioxidants
Rationale
PE has been described as a two stage process:
1. reduced placental perfusion followed by
2. 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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50. 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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51. 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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52. 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.
III. OTHER
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53. 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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54. 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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55. 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 exercise=any 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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56. 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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57. 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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58. 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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59. 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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60. 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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61. 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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62. 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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63. 250 lectures
3092 members
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