Prediction, Prevention, and Prognosis of Preeclampsia: Recommendations
Prediction, Prevention, and Prognosis of Preeclampsia: Recommendations
Prediction, Prevention, and Prognosis of Preeclampsia: Recommendations
Chapter 2
In the UK, the strongest clinical markers of preeclampsia There is a considerable literature devoted to the prevention
risk that are identifiable at antenatal booking (i.e., those of preeclampsia. However, there is some controversy over
shaded in Table 4), have been recommended as a means of whether or not prevention of preeclampsia per se is a wor-
screening for preeclampsia in the community (the thy goal, rather than the prevention of the complications of
preeclampsia community guidelines, PRECOG).108 It is preeclampsia. Non-severe gestational hypertension (or
recommended that women should be offered subspecialty preeclampsia specifically) may have some adaptive func-
referral if they have one of the bolded (and shaded markers) tion.134 For example, neonatal morbidity is lower and
or two or more of the unbolded (and shaded markers) neurodevelopmental outcome better among SGA babies
(grade D) (Table 4). whose mothers become hypertensive than among those
whose mothers do not.135 Therefore, we have based our
The markers of preeclampsia risk that become available in
recommendations on both the prevention of preeclampsia
the second and third trimesters are based on the
and/or the prevention of its associated complications.
pathophysiological changes that characterize preeclampsia
and precede clinical disease. Risk markers that are best char- Using the PRECOG criteria, women are stratified, at book-
acterized are presented in Table 4. Many have been evalu- ing, as being at low or increased risk of preeclampsia on
ated, and they include measures of the following: placental basis of the presence (Table 4) of one of the bolded (and
perfusion and vascular resistance (e.g., mean second trimes- shaded) markers, or two or more of the unbolded (and
ter BP, intravenous infusion of angiotensin-II, roll-over shaded) markers (expert opinion).108 This approach does
* Those risk markers of greatest importance are highlighted in shades of grey. Women at increased risk (who should be considered for specialty referral) are those
with one of the bolded (and shaded) factors, or two or more of the unbolded (and shaded) markers. 108
Elevated BP is defined as dBP =110 mmHg before 20 weeks,68 2nd trimester mean arterial pressure of 85 mmHg, or a 2nd trimester sBP 120mmHg.109
Standardized cut-offs for 24-hour ambulatory BP or home BP monitoring have not been established.
Subfertility and its treatment (especially the use of donor eggs, sperm and/or gametes), after correction for multiple gestations.
Decreased first trimester PAPP-A (pregnancy-associated plasma protein A) 5th centile,110 unexplained increased second trimester AFP (alphafetoprotein), 111-116
increased second trimester hCG, 114-117 increased first or second trimester inhibin A, 113,118-121 increased second trimester activin. 122
Abnormality is practically defined at 22-24 weeks as bilateral notching with mean resistance index (RI) > 0.55 (i.e., > 50th centile), unilaternal notching with mean
RI > 0.65 (> 90th centile), or no notching with mean RI > 0.70 (> 95th centile). 123
Heritable thrombophilia includes Factor V Leiden gene mutation and Protein S deficiency.
** Investigational markers include elevated sFlt-1/P1GF (soluble fms-like tyrosine kinase, placental growth factor),124-126 PAI-1/PAI-2 (plasminogen activator
inhibitor),124,127 von Willebrand factor,128 and leptin.122,125,129
MSS: maternal serum screening; UTI: urinary tract infection
not recognize nulliparous women as requiring specialist for maintenance of fitness, (I, A) periconceptual use of a
consultation unless another risk marker for preeclampsia is folate-containing multivitamin for prevention of neural
present. tube defects, (I, A) and smoking cessation for prevention
of low birthweight and preterm birth. (I, E)
Preventing Preeclampsia and its Complications in 3. The following may be useful: periconceptual use of a
Women at Low Risk
folate-containing multivitamin, (I, B) or exercise. (II-2, B)
Recommendations
4. The following are not recommended for preeclampsia
1. Calcium supplementation (of at least 1g/d, orally) is rec- prevention, but may be useful for prevention of other
ommended for women with low dietary intake of cal- pregnancy complications: prostaglandin precursors, (I,
cium (< 600 mg/d). (I, A) C) or supplementation with magnesium, (I, C) or zinc. (I, C)
2. The following are recommended for other established 5. The following are not recommended: dietary salt restric-
beneficial effects in pregnancy: abstention from alcohol tion during pregnancy, (I, D) calorie restriction during
for prevention of fetal alcohol effects, (II-2, E) exercise pregnancy for overweight women, (I, D) low-dose
Table 5. Risk stratification for preeclampsia and intensity of antenatal care: EMMA Clinic, Vancouver
No. of abnormal
Risk Nature of previous PET MSS analytes Uterine artery Dopplers Routine antenatal care PLUS
*For growth, amniotic fluid index and umbilical artery Doppler monthly.
For growth, amniotic fluid index and umbilical artery Doppler every two weeks.
EMMA: estimate of maternal markers of adverse outcome; MSS: maternal serum screening; PET: preeclamptic toxemia
aspirin, (I, E) vitamins C and E (based on current evi- stimulating release of parathyroid hormone or renin,
dence), (I, E) or thiazide diuretics. (I, E) thereby increasing vascular smooth muscle intracellular cal-
6. There is insufficient evidence to make a recommendation cium.143 Oral calcium supplementation (of at least 1g/d)
about the following: a heart-healthy diet, (II-2, I) work- decreases the incidence of preeclampsia (RR 0.68; 95% CI
load or stress reduction, (II-2, I) supplementation with 0.490.94) (7 trials including the American CPEP trial,144
iron with/without folate, (I, I) or pyridoxine. (I, I). 14 619 women), due to a small decrease among women
with low calcium intake (RR 0.81; 95% CI 0.670.99) (4 tri-
Comments als, 9775 women).142 Maternal death or serious morbidity
was also reduced (RR 0.80; 95% CI 0.650.97) (1 trial, 8312
Abstention From Alcohol women).145 The use of calcium supplementation may have
There are no trials on the effect that abstention from alco- been discouraged by the results of the largest (low-risk)
hol has on the incidence of HDPs, although reduced con- CPEP trial, in which calcium supplementation was not
sumption is recommended to reduce BP in non-pregnant effective in a low-risk, nulliparous population with adequate
individuals.69 There is no proven safe level of alcohol con- dietary calcium.144 There were no documented adverse
sumption in pregnancy.136 effects of calcium supplementation.142 An alternative to
supplementation may be an increase in dietary calcium
Aspirin (Low-Dose) intake, by 3 to 4 dairy servings per day (as one serving corre-
Low dose aspirin does not decrease the incidence of sponds to 250300 mg of calcium).
preeclampsia in low risk nulliparous women (RR 0.93;
95% CI 0.811.08).137141
Dietary Changes
Calcium
There is an inverse relationship between dietary calcium
intake and BP in the general population.142 Low calcium Dietary salt restriction (with confirmed compliance) does
intake (< 600 mg/day, corresponding to less than two dairy not affect the incidence of gestational hypertension or
servings per day) may do harm by causing vasoconstriction, preeclampsia specifically (RR 1.11; 95% CI 0.462.66)
either through increasing magnesium levels or by (2 trials, 603 women).146
A heart-healthy diet has been associated with a lower risk of nerves. Magnesium supplementation (various prepara-
preeclampsia in a case-control study.147 No trials of this tions), primarily in women at low risk, did not affect the
intervention were identified. incidence of a HDP, but did decrease preterm birth (RR
Energy or protein restriction for women who are over- 0.73; 95% CI 0.570.94), low birthweight (RR 0.67; 95% CI
weight or for those with excessive weight gain in pregnancy 0.460.96), and incidence of SGA infants (RR 0.70; 95% CI
did not result in a decreased incidence of preeclampsia or 0.530.93) (7 trials, 2689 women).166 However, no conclu-
gestational hypertension (3 trials, 384 women).148 There are sions can be drawn because only one included trial was of
theoretical concerns about the effect of starvation ketosis high quality.
on fetal neurodevelopment.149
Zinc plays a critical role in protein synthesis and nucleic acid
Folate-Containing Multivitamins metabolism. Zinc supplementation (2090 mg elemental
Periconceptual use of a folate-containing multivitamin is zinc) primarily in women at low risk did not affect the inci-
recommended for all women for primary prevention of dence of a HDP, although decreases in preterm delivery
neural tube and, possibly, other congenital anomalies, (RR 0.73; 95% CI 0.540.98) and CS (RR 0.69; 95% CI
including cardiovascular and limb defects.150 0.490.96) reached statistical significance (7 trials, 1962
Periconceptual and ongoing regular use of multivitamins women).165
has been associated with primary prevention of gestational
hypertension (1 trial, 138 women)151 and preeclampsia in Prostaglandin Precursors
women with a body mass index < 25 kg/m2 (prospective
Diets rich in marine oils are associated with a reduced risk
cohort, 1835 women).152 (See below for use of vitamins C
of preeclampsia.168 Marine and other oils (e.g., evening
and E for women at increased risk of preeclampsia.)
primrose oil) are rich in prostaglandin precursors and may
Lifestyle Changes be beneficial by reducing inflammation and
Observational studies have associated exercise (and greater vasoconstriction. These oils (referred to as prostaglandin
intensity of exercise) with a reduced risk of precursors for brevity) did not decrease the risk of
preeclampsia.153158 Potential mechanisms include a preeclampsia in mixed populations that included both low
decrease in BP, in lipids, and in proinflammatory and high risk women (RR 0.86; 95% CI 0.591.27) (6 trials,
cytokines.159 We were unable to identify trials of exercise for 2783 women).168 However, birth before 34 weeks was mar-
preeclampsia prevention among women at low risk. How- ginally decreased (RR 0.69; 95% CI 0.490.99). Although
ever, exercise of low to moderate intensity is beneficial for marine oil supplementation may be useful, increased dietary
general health reasons to maintain or improve physical fit- intake of fish for the purpose of fish oil consumption, is not
ness (11 trials, 472 women).160 Overweight women who recommended because of concerns about contaminants
exercised from early pregnancy had improved exercise such as mercury.169
capacity without demonstrated differences in substantive
clinical outcomes (1 trial, 132 women).161 Smoking Cessation
Preeclampsia is associated with greater workload157,162
and Smoking is associated with a reduced risk of preeclampsia
stress,163 even among women at low risk, but the quality of in observational studies. However, smoking cessation is
the evidence does not allow for firm conclusions.164 recommended to decrease low birthweight (RR 0.81; 95%
Although workload reduction is a common obstetric inter- CI 0.700.94) and preterm birth (RR 0.84; 95% CI 0.72
vention, we were unable to identify randomized studies of 0.98) (57 trials, 28 431 women).170 Various approaches have
workload or stress reduction on the incidence of been tried. An ongoing RCT is evaluating the effectiveness
preeclampsia. These are unlikely to be forthcoming given and safety of nicotine replacement therapy in pregnancy.171
the nature of the interventions.
95% CI 128909 women) (51 trials, 36 500 women over- secondary analysis of the VIP (vitamin C and E trial) in the
all).180 There is no evidence of short- or long-term adverse UK.188 Periconceptual use of a folate-containing multivita-
effects on the mother or newborn. Aspirin does not min is recommended for all women of child-bearing age for
increase miscarriage risk.181 prevention of neural tube and, possibly, other birth defects.
Who should receive aspirin and in what dose is unclear.
Subgroup analyses in meta-analyses of aspirin trials appear Heparin
to indicate that aspirin may be more effective for women at Enthusiasm for the use of heparin to prevent preeclampsia
greatest baseline risk when it is started before 16 weeks ges- and other adverse placental complications comes from the
tation and when aspirin is used at a higher dose.180,182,183 effective use of unfractionated heparin for women with
This may be because some women are more resistant than antiphospholipid syndrome and recurrent pregnancy
others to the effects of aspirin,184 and/or a dose of at least loss.189 It is unclear whether or not heparin does more harm
75 mg/d may be necessary to inhibit both platelet and pla- than good for women with a history of preeclampsia, even
cental thromboxane. However, a dose of 100 mg/d may in women with an inherited or acquired thrombophilia.
affect fetal prostacyclin synthesis.185 One RCT found that There are no completed trials of heparin for preeclampsia
taking aspirin at bedtime resulted in lower BP than taking prevention in women with thrombophilia.190 The only trial
aspirin in the morning.180,186 Aspirin may be continued until in women without thrombophilia enrolled 80 women with
delivery187 (see Anaesthesia and Fluid Administration). the angiotensin-converting enzyme DD polymorphism. In
this trial, LMWH (dalteparin 5000 IU/d) decreased
Calcium preeclampsia recurrence by 75%.191 Potential benefits of
Oral calcium supplementation (of at least 1g/d) decreases thromboprophylaxis must be weighed against the cost,
the incidence of preeclampsia (RR 0.22; 95% CI 0.120.42) inconvenience, and possible side effects of treatment. Prac-
and preterm delivery (RR 0.45; 95% CI 0.240.83) (5 trials, titioners are encouraged to enrol their patients in clinical tri-
587 women).142 Three trials were conducted in low calcium als (e.g., TIPPS192).
intake populations. No trial included women with previous
preeclampsia. There were no documented adverse effects Lifestyle Changes
of calcium supplementation. An alternative to There is robust epidemiological data that weight gain
supplementation may be an increase in dietary calcium between pregnancies (even in non-obese women) is associ-
intake, by 3 to 4 dairy servings per day (as one serving corre- ated with significantly more preeclampsia and other preg-
sponds to 250300 mg of calcium). nancy complications, such as CS and gestational diabetes.193
womens views) were not reported. There is a lack of clarity PROGNOSIS (MATERNAL AND FETAL) IN PREECLAMPSIA
about the definition of bed rest and uncertainty about Recommendations
whether women comply with activity restriction.197
1. Serial surveillance of maternal well-being is recom-
mended, both antenatally and post partum. (II-3, B)
Micronutrients Other Than Calcium
2. The frequency of maternal surveillance should be at least
Magnesium supplementation (various preparations) admin- once per week antenatally, and at least once in the first
istered to a mixed population of women at low and high risk three days post partum. (III, C)
in (7 trials, 2689 women) did not decrease the risk of 3. Serial surveillance of fetal well-being is recommended.
preeclampsia, but decreases were seen in preterm birth (RR (II-2, B)
0.73; 95% CI 0.570.94), low birth weight (RR 0.67; 95% CI
0.460.96), and incidence of SGA infants (RR 0.70, 95% CI 4. Antenatal fetal surveillance should include umbilical
0.530.93).166 However, no conclusions can be drawn artery Doppler velocimetry. (I, A)
because only one included trial was of high quality. 5. Women who develop gestational hypertension with nei-
ther proteinuria nor adverse conditions before 34 weeks
In one trial (100 women), selenium supplementation in the should be followed closely for maternal and perinatal
third trimester was reported to decrease gestational hyper- complications. (II-2, B)
tension, but this was not defined.198 Comments
Garlic may decrease lipid peroxidation and platelet aggrega- Women with preeclampsia should undergo serial maternal
tion. In a small trial of 100 women at increased risk of and fetal surveillance of well-being. However, the nature of
preeclampsia based on a positive roll-over test, no impact of surveillance (and its frequency), particularly among women
garlic was seen on preeclampsia; garlic supplementation was undergoing expectant management of preeclampsia, has
association with more reports of odour than was placebo.199 not been defined. Table 3 presents a list of suggested inves-
tigations, based on detection of end-organ dysfunction. A
We did not identify trials of zinc, pyridoxine, iron comprehensive program of maternal and fetal evaluation
(with/without folic acid), zinc, multivitamins with/without (that included all of the tests recommended in Table 3)
micronutrients, vitamin A, iodine, or copper for decreased adverse maternal outcomes from 5.1% to 1.2%
preeclampsia prevention in women at increased risk. in one tertiary perinatal centre.204 Maternal surveillance
should continue post partum because of the risk of
postpartum deterioration, particularly when there are
Prostaglandin Precursors
end-organ complications of preeclampsia.205
Prostaglandin precursors did not decrease the risk of Maternal surveillance
preeclampsia in mixed populations of women at low and In a 1999 survey, at least 80% of Canadian obstetric care
high risk (RR 0.87; 95% CI 0.591.28) (5 trials, 1683 providers reported using complete blood count, coagula-
women).168 Birth before 34 weeks was marginally decreased tion tests, serum creatinine, serum uric acid, aspartate and
(RR 0.69; 95% CI 0.490.99). alanine aminotransferases, lactate dehydrogenase, urinary
dipstick proteinuria, and 24-hour urinary protein.206 These
Vitamins C and E were performed at least once each week (and rarely daily).
Vitamins C (1000 mg/d) and E (400 IU/d) decreased the Among women with proteinuria, higher (vs. lower) levels of
risk of preeclampsia in one200 of two small pilot RCTs (2 tri- proteinuria have not been consistently associated with
als, 483 women).200,201 Another small RCT found a higher maternal or perinatal mortality or morbid-
decreased risk of preeclampsia with administration of mul- ity,17,70,207209and have not predicted short-term maternal
tiple antioxidants (including vitamins C and E) in women renal failure or ongoing proteinuria.208211 However, given
who had a low superoxide dismutase levels (1 trial, 60 the central role of proteinuria in preeclampsia, we are
women).202 However, in an adequately powered RCT in unwilling to recommend against use of protein quantifica-
women at high risk (VIP Trial203), vitamins C and E did not tion (by any method) until further data are available.
decrease the incidence of preeclampsia; rather, vitamins C Fetal surveillance
and E were more frequently associated with birthweight In general, a program of antepartum fetal assessment
< 2.5 kg.203 The (high risk arm of the) INTAPP trial of vita- reduces perinatal morbidity and/or mortality in women
mins C and E before 18 weeks in women at increased risk of with HDP.212 In general, few trials have compared these
preeclampsia was stopped early but data are pending.174 techniques, and no one technique appears to be superior.
For gestational hypertension or preeclampsia specifically, (88%), or umbilical artery Doppler velocimetry (56%); and
use of umbilical artery Doppler velocimetry appears to less than once weekly ultrasonographically estimated fetal
decrease perinatal mortality (OR 0.71; 95% CI 0.501.01) weight.
(11 trials, nearly 7000 women).213,214 Weekly Doppler inter-
rogation of the umbilical artery is suggested as reasonable
clinical practice. Gestational Hypertension
In the 1999 survey by Caetano et al. (see Maternal surveil- Approximately 35% of women with gestational hyperten-
lance), at least 80% of Canadian obstetricians reported using sion with onset at < 34 weeks develop preeclampsia,2126
kick count, non-stress test/cardiotocography, and biophys- and the associated risks of serious maternal (2%) and
ical profile.206 Compared with maternal surveillance, there is perinatal complications (16%) are high.24 These women
less consistency regarding frequency of fetal testing: daily should receive heightened maternal and fetal surveillance,
kick counts daily (83%); at least weekly NST (65%), BPP the nature and frequency of which has not been established.