Incidence and Risk Factors

Preeclampsia often affects young and nulliparous women, whereas older

women are at greater risk for chronic hypertension with superimposed
preeclampsia. Also, the incidence is markedly influenced by race and
ethnicityand thus by genetic predisposition. Other factors include
environmental, socioeconomic, and even seasonal influences (Lawlor,
2005; Palmer, 1999; Spencer, 2009, and all their co-workers).
With consideration for these vicissitudes, in a number of worldwide studies
reviewed by Sibai and Cunningham (2009), the incidence of preeclampsia
in nulliparous populations ranges from 3 to 10 percent. The incidence of
preeclampsia in multiparas is also variable but is less than that for
nulliparas. However, Ananth and Basso (2009) reported that the risk for
stillbirths was more likely in hypertensive multiparas compared with
nulliparas.
Other risk factors associated with preeclampsia include obesity, multifetal
gestation, maternal age older than 35 years, and African-American
ethnicity (Conde-Agudelo and Belizan, 2000; Sibai and colleagues, 1997;
Walker, 2000). The relationship between maternal weight and the risk of
preeclampsia is progressive. It increases from 4.3 percent for women with
a body mass index (BMI) < 20 kg/m2 to 13.3 percent in those with a BMI >
35 kg/m2. In women with a twin gestation compared with those with
singletons, the incidence of gestational hypertension13 versus 6
percent, and the incidence of preeclampsia13 versus 5 percent, are both
significantly increased (Sibai and co-workers, 2000). The incidence is
unrelated to zygosity (Maxwell and associates, 2001).
Although smoking during pregnancy causes a variety of adverse
pregnancy outcomes, ironically, it has consistently been associated with a
reduced risk of hypertension during pregnancy (Bainbridge and
associates, 2005; Zhang and colleagues, 1999). Placenta previa has also
been reported to reduce the risk of hypertensive disorders in pregnancy
(Ananth and colleagues, 1997).
In the woman who was normotensive during her first pregnancy, the
incidence of preeclampsia in a subsequent pregnancy is lower than cited
above. In a population-based retrospective cohort analysis, Getahun and
colleagues (2007) studied almost 137,000 second pregnancies in such
women. The incidence for preeclampsia in white women was 1.8 percent
compared with 3 percent in African-American women. Again, obesity was
a major risk factor.

Etiopathogenesis

Any satisfactory theory concerning the etiology and pathogenesis of

preeclampsia must account for the observation that gestational
hypertensive disorders are more likely to develop in women who:

Are exposed to chorionic villi for the first time

Are exposed to a superabundance of chorionic villi, as with twins or

hydatidiform mole

Have preexisting renal or cardiovascular disease

Are genetically predisposed to hypertension developing during

pregnancy.

A fetus is not a requisite for preeclampsia. And although chorionic villi are
essential, they need not be located within the uterus. For example, Worley
and associates (2008) reported a 30-percent incidence in women with an
extrauterine pregnancy exceeding 18 weeks' gestation. Regardless of
precipitating etiology, the cascade of events that leads to the
preeclampsia syndrome is characterized by a host of abnormalities that
result in vascular endothelial damage and subsequent vasospasm,
transudation of plasma, and ischemic and thrombotic sequelae.
Preeclampsia as a Two-Stage Disorder
Observations that abnormal interfaces between maternal, paternal, and
fetal tissues may cause preeclampsia have led to hypotheses that the
syndrome is a two-stage disorder. In this scenario, there is a spectrum to
include "maternal and placental preeclampsia" (Ness and Roberts, 1996).
According to Redman and colleagues (2009), stage 1 is caused by faulty
endovascular trophoblastic remodeling that downstream causes the
stage 2 clinical syndrome (Fig. 34-1). There certainly is evidence that
some cases of preeclampsia fit this theory. Importantly, stage 2 is
susceptible to modification by preexisting maternal conditions that include
cardiac or renal disease, diabetes, obesity, or hereditary influences. Such
compartmentalization seems artificial, and it seems logical that there
likely is a continuous process. Thus, although perhaps helpful to classify
the syndrome for research purposes, preeclampsia is clinically more
realistically a continuum of worsening disease. Moreover, evidence is
accruing that many "isoforms" exist as discussed below.

Etiology
Writings describing eclampsia have been traced as far back as 2200 BC (Lindheimer and
colleagues, 2009). And an imposing number of mechanisms have been proposed to explain its
cause. Instead of being simply "one disease," preeclampsia appears to be a culmination of

factors that likely involve a number of maternal, placental, and fetal factors. Those currently
considered important include:
1. Placental implantation with abnormal trophoblastic invasion of uterine vessels
2. Immunological maladaptive tolerance between maternal, paternal (placental), and
fetal tissues
3. Maternal maladaptation to cardiovascular or inflammatory changes of normal
pregnancy
4. Genetic factors including inherited predisposing genes as well as epigenetic
influences.
Abnormal Trophoblastic Invasion
In normal implantation, shown schematically in Figure 34-2, the uterine spiral arterioles
undergo extensive remodeling as they are invaded by endovascular trophoblasts (see also
Chap. 3, Invasion of Spiral Arteries). These cells replace the vascular endothelial and
muscular linings to enlarge the vessel diameter. The veins are invaded only superficially. In
preeclampsia, however, there may be incomplete trophoblastic invasion. With such shallow
invasion, decidual vessels, but not myometrial vessels, become lined with endovascular
trophoblasts. The deeper myometrial arterioles do not lose their endothelial lining and
musculoelastic tissue, and their mean external diameter is only half that of vessels in normal
placentas (Fisher and colleagues, 2009). Madazli and associates (2000) showed that the
magnitude of defective trophoblastic invasion of the spiral arteries correlates with the severity
of the hypertensive disorder.