Updates in Pre-eclampsia Preventions

Rudy Setiady
Medicine Faculty, Universitas Kristen Krida Wacana
Alamat : Medicine Faculty - Universitas Kristen Krida Wacana, Jalan Arjuna Utara Nomor 6, Kebon
Jeruk Jakarta Barat 11510
email : setiadyrudy@hotmail.com
Introduction
Hypertensive disorders of pregnancy are an important cause of severe morbidity,
longterm disability, and death among both mothers and their babies. Pre-eclampsia stands out
among the hypertensive disorders for its becoming an increasingly common diagnosis in
developed world (10 to 18 %).1 Pre-eclampsia is defined as the association of pregnancy
induced hypertension and proteinuria of 300 mg/24 hours after 20 weeks gestation. 2 Pre-
eclampsia was first recognized almost 2000 years ago.3 In ancient Greece, there was already a
description of the disease.3 But, until now, pre-eclampsia still the one of causes of maternal
and perinatal mortality and morbidity worldwide. Many factors complicate the prevention of
pre-eclampsia cases. Most are attributed to unclear etiology, the low predictive value of
current screening test and the several presentations of the disease. 4 Because of that,
optimizing health care to prevent women with pre-eclampsia is a necessary step towards
achieving the Millenium Development Goals. Obstetric management has also been directed at
disease prevention. Prevention of pre-eclampsia is an ongoing challenge. Prevention of pre-
eclampsia may be primary, secondary, and tertiary.5 Many strategies based on antenatal care,
change in lifestyle related to the effect of rest or advice to reduce physical activity, nutritional
supplementation and drugs as a treatment to avoid pre-eclampsia complications have been
studied.3,5 Primary prevention involves avoiding pregnancy in women at high risk for pre-
eclampsia. Secondary prevention is based on interruption of known pathophysiological
mechanism of the disease before its establishment. And tertiary prevention relies on using
treatment to avoid pre-eclampsia complications. Therefore, tertiary prevention can be
difficult to achieve without exposing many to possibly unnecessary risks. Given the above,
the aim of this paper is to review about primary and secondary prevention of pre-eclampsia.5

Primary prevention
Many different approaches to prevent pre-eclampsia have been investigating for
decades. Primary preventions are recommended for women who intend to be pregnant, it
reduces the predisposing factors such as maintaining weight and modifying lifestyles before
pregnancy, avoiding pregnancy in extreme age( <18 years old or >35 years old). Improving
the nutritions intakes in the pregnancy like consumption of supplement and vitamis still
controversial because thats no evidence in the reduction of preeclampsia incident.

Lifestyle modification
Women with a BMI > 35 kg/m2 in early pregnancy increased the high risk of pre-
eclampsia. Obesity and pre-eclampsia share several features, including subclinical
inflammation, insulin resistance and lipotoxicity.6,7 Lipotoxicity is associated with maternal
vascular dysfunction and reduced trophoblast invasion into the developing placenta; it has
been proposed to link maternal overweight and obesity to the risk of pre-eclampsia. 6 It has
also been hypothesised that maternal obesity may increase the risk of pre-eclampsia by
reducing endogenous production of nitric oxide, with the subsequent increased risk of
endothelial dysfunction.7 Obesity is associated with increased insulin resistance and elevated
glucose concentration.
For all the same reasons that they are important in pregnancy, these interventions need
also to be extended or modified for application to the preconception and postpartum periods.
Lifestyle interventions for weight control can be divided into those that are diet-based,
physical-activity-based, and a mixture of diet-based and physical-activity-based. High-quality
antenatal dietary and lifestyle intervention trials in pregnant women who are overweight or
obese, alone or in combination with drugs, do not limit gestational weight gain to the degree
required to have a meaningful impact on pregnancy and birth outcomes, or reduce the
incidence of gestational diabetes. exercise interventions which need physical efforts were
most commonly of moderate intensity involving walking, dance, or aerobic classes.5

Dietary recommendations were tailored to the womans habitual diet, and were
designed to reduce glycaemic load, reduced dietary glycaemic load, energy intake,
carbohydrate, and total fat, and increased protein and fibre intake and physical activity were
reported in the intervention group compared with the control group, and a modest but
significant 06 kg reduction. This conclusion suggests that maternal overweight and obesity
are best addressed across the entire reproductive life cycle and that all women of childbearing
age need to be encouraged to adopt healthy diets and lifestyles before and between
conceptions. Behavioural support for diet and lifestyle improvement like problem-solving, set
goals, self-monitor, and enlist social support in attempting to develop a healtier pattern of
eating are also important things for maintaining the weight before pregnancy.5
 Pharmacological and other interventions Women who are overweight or obese enter
pregnancy in a state of increased insulin resistance, which raises the possibility that drugs
such as metformin could be used as an adjunct therapy to improve insulin sensitivity and the
pattern of fetal growth. In randomised trials 8, 9
of metformin in pregnant women who are
obese but do not have pre-existing diabetes, the drug did not have a beneficial effect on off
spring birthweight, gestational weight gain, gestational diabetes, or on the combined fetal and
neonatal outcomes of stillbirth, termination of pregnancy, miscarriage, and neonatal death.
Nutritional supplements such as probiotics have been given in pregnancy because of their
potential beneficial effects on the gut microbiome, resulting in modification of
lipopolysaccharides and insulin sensitivity. The results of a randomised trial suggested that
probiotic administration from the first trimester until the end of breastfeeding alongside
dietary intervention helped to reduce gestational diabetes. However, in another study,10 a 4
week course of probiotics during pregnancy in women who are obese did not improve
glycaemic status compared with that of those who did not receive the intervention.

Avoiding pregnancy in high risk age

Pre-eclampsia is more common at the extremes of maternal age (<18 years or >35
years old). Some studies reported that pregnant women aged 35 years old are at increased
risk of Pre-eclampsia. In a review of risk factors for Pre-eclampsia, women older than 40
years had almost twice the risk of developing pre-eclampsia compared with younger women.
their pregnancies were more likely to be complicated by preterm deliveries and impaired fetal
growth. As a consequence, the need for neonatal intensive care was significantly higher for
women of advanced maternal age, suggesting a substantial increase in the use of healthcare
resources. It makes sense to prepare the pregnancy between 18 35 years old.11

Smoking
The mechanism for the protective effect of cigarette smoking on pre-eclampsia is
unknown but cannot be explained by nicotine, confounding factors, and changes in placental
morphologic or histopathologic characteristics.3 Some investigators have hypothesized that
carbon monoxide (CO) produced by cigarette smoking may be the substance that underlies
the negative association. This study shows that maternal low-dose treatment with CO can
prevent the HTN and proteinuria in a PE-like mouse model induced by AdsFlt-1 injection.12, 13
However, smoking is only protective against pre-eclampsia in women without pre-gestational
hypertension, and even then principally among younger women.
The most commonly accepted theory for the development of preeclampsia is that poor
placental development and inadequate trophoblast-mediated remodeling of the spiral
arterioles results in reduced placenta perfusion, which increases oxidative stress, resulting in
the release of antiangiogenic factors causing maternal systemic endothelial dysfunction. We
propose that cigarette smoking enhances placental trophoblast invasion (by increasing
cellular production of Adrenomullin), which may improve placental function and improve
spiral arteriole remodeling, thereby decreasing placental release of antiangiogenic factors,
which have been implicated in preeclampsia.12 Multiple studies have demonstrated that
smoking during pregnancy reduces the risk of developing preeclampsia by approximately
50%. The risk reduction did not apply to women who smoked in the first trimester but quit by
the onset of the third trimester, rather smoking throughout pregnancy provided greatest
protection. Moreover, the same group found that the use of smokeless tobacco conferred no
protection from preeclampsia. Finally, our group has shown that nicotine treatment of
trophoblast cells did not affect cell viability, migration, or AM (Adrenomedullin) production,
while CSE (Cigarette Smoke Extract) treatment enhanced cellular viability and migration,
both of which were dependent on AM. These findings suggest that smoking throughout
pregnancy is required to maintain protection, and that nicotine products do not provide
similar protection.12
Cigarette smoking has also been shown to affect other angiogenic markers that are
implicated in preeclampsia. Soluble fms-like tyrosine kinase 1 (s-Flt1) is the soluble form of
the vascular endothelial growth factor (VEGF) receptor. The s-Flt1 binds free serum VEGF,
preventing VEGF signaling, thereby acting as a VEGF antagonist. Women with preeclampsia
have been found to have elevated levels of s-Flt1, whereas pregnant smokers have lower
levels of s-Flt1.38 Furthermore, there is a reduction in the secretion of s-Flt1 from term
placental explants treated with CSE in culture. Together, this suggests that in addition to the
effects of AM on trophoblast function, cigarette smoking also likely decreases the risk of
preeclampsia by its affect on serum angiogenic factors.12

Secondary prevention
Secondary preventions is based on interruption of known pathophysiological
mechanism of the disease before its establishment. Its aimed for the women during
pregnancy. Many approaches have done to prove that pre-eclampsia can be prevented.
Calcium
It has been proposed that low-calcium intake may increase blood pressure by
stimulating either parathyroid hormone or renin release, increasing intracellular calcium in
vascular smooth muscle and leading to vasoconstriction. Calcium supplementation may
reduce parathyroid release and could reduce smooth muscle contractility. It could also reduce
uterine smooth muscle contractility or increase serum magnesium levels and thus prevent
preterm labour and delivery. Recently, a lower resistance index by Doppler in uterine and
umbilical arteries in pregnant women with calcium supplementation has been demonstrated. 14
Calcium supplementation ( 1 g/day) is associated with a significant reduction in the risk of
pre-eclampsia, particularly for women with low calcium diets. The treatment effect may be
overestimated due to small-study effects or publication bias. It also reduces preterm birth and
the occurrence of the composite outcome 'maternal death or serious morbidity'. The World
Health Organization recommends calcium 1.5 g to 2 g daily for pregnant women with low
dietary calcium intake.14

The limited evidence on low-dose calcium supplementation suggests a reduction in

pre-eclampsia, but needs to be confirmed by larger, high-quality trials. Pending such
results, in settings of low dietary calcium where high-dose supplementation is not feasible,
the option of lower-dose supplements (500 to 600 mg/day) might be considered in
preference to no supplementation.15

Aspirin
During placental development trophoblastic invasion of the spiral arteries occurs from
8 to 1620 weeks of gestation.Defective placentation leads to inadequate uteroplacental blood
perfusion and ischemia, resulting in maternal vascular to endothelial dysfunction, with
platelet and clotting system activation. These issues support the hypothesis that antiplatelet
agents might prevent preeclampsia. Low-dose aspirin could inhibit thromboxane-mediated
vasoconstriction, prevent failure of physiological spiral artery transformation and, thus,
minimize development of preeclampsia. In the first trials, treatment started relatively late in
pregnancy (after 18 to 20 weeks) and some of them included low-risk patients, resulting in no
evidence of benefit. Researchers wondered if better results could be obtained with earlier
treatment directed at high risk groups.4
 In some studies, low dose aspirin (60 to 150mg) reduced the risk of late-onset pre-
eclampsia in high-risk women when initiated early in pregnancy. To optimize pregnancy
outcome in women at increased risk for pre-eclampsia giving low dose aspirin prior to 17w0d
may be initiated.16, 17

Low Molucular Weight Heparin

The mechanism of action of prophylactic LMWH for the possible prevention of
severe pre-eclampsia is currently unknown because of the predominantly clinical end points
of previous trials. The mechanism of LMWH is commonly attributed to an anticoagulant
action of heparin within the placenta, although the major trials did not include assessment of
the placenta after delivery and improved outcomes are observed in at-risk women without
demonstrable thrombophilia disorders. Therefore, the mechanism of action of heparin for the
prevention of pre-eclampsia remains elusive.18
An alternative hypothesis to an anticoagulant action is that LMWH exerts direct
vascular actions in the maternal compartment to reverse the placenta-mediated systemic
vascular dysfunction characteristic of pre-eclampsia. Family history of hypertension and
other cardiovascular disorders significantly increases the risk of pre-eclampsia, suggesting a
predisposition to vascular dysfunction. In line with these observations, numerous studies have
concluded that women who subsequently develop pre-eclampsia demonstrate impaired
endothelium-dependent vasodilation early in pregnancy. Abnormal vascular function has been
shown to persist postpartum after pre-eclampsia, and it may provide an explanation for the
significant risk of cardiovascular disease later in life. Indeed, an important outstanding
question is whether abnormal endothelial biology is a cause or a consequence of pre-
eclampsia disorders.18
Combination with low dose aspirin started in early pregnancy is superior to low-dose
aspirin alone for the prevention of early-onset pre-eclampsia and the delivery of a small for
gestational age neonate. Larger clinical trials and more studies, including women at risk of
pre-eclampsia, should consider combining LMWH with aspirin for its prevention.18, 19

Metformine
Metformin for the prevention of pre-eclampsia, especially in obese pregnant women.
A research of this complex disease identified the high risk of pre-eclampsia identification
group population are pre pregnancy obesity (BMI over 30).20
 In interesting study used metformin (a save and proven drug for diabetic pregnant
women) in a dose of 3.0 g/day in obese pregnant women without diabetes mellitus,
potentially to prevent a case of pre-eclampsia.21 As a result, metformin can inhibit hypoxic
inducible factor 1 by reducing mitochondrial electron transport chain activity. It reduced
soluble fms-like tyrosine kinase 1 and soluble endoglin secretion from primary human
tissues. Thats related with hypotheses of pre- eclampsia is associated with placental
ischemia/hypoxia, which leads to release of soluble fms-like tyrosine kinase I (sFlt-1) and
soluble endoglin (sENG). On the other hand, metformin also improved features of endothelial
dysfunction relevant to preeclampsia, enhanced vasodilation in omental arteries, and induced
angiogenesis. Because of that, metformin has potential to prevent or treat preeclampsia.22

Conclusion
The incident of pre-eclampsia is the most high in the pregnancy. Its known for a long
time ago and needs the quick and precise management. There are tow main preventions in
pre-eclampsia i.e primary and secondary preventions. Interventions in pre-eclampsia still
need more approaches especially in drugs. Drugs interventions like low dose aspirin, low
moluecular weight heparin and the combination with LDA, calcium supplement for low
intake populations, Metformin show promise in the interventions. The result in large clinical
trials shows progress in prevention of pre-eclampsia.

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