Pre-eclampsia is a disease of many risk factors and theoretical speculations.
It is, for unknown reasons, more prevalent among primiparous women. Some observations show that a change of sexual partner before the next pregnancy increases the risk, but this association disappears when correction is made for time interval since the last birth. Risk factors may be pregnancy-specific, such as twinning or mole, whereas others are linked to the woman, such as obesity and diabetes. Genetic risk factors are being searched for, but as yet with relatively little success. A previous pregnancy complicated by pre-eclampsia is probably the strongest risk factor. For practical purposes, women at increased risk can be identified and should be followed closely. No effective primary preventative action is available. Prevention of the serious consequences of pre-eclampsia still relies on early detection of increases in blood pressure and proteinuria.
Background
Pre-eclampsia is a multi-systemic syndrome usually recognised by new-onset hypertension and proteinuria in the second half of pregnancy. The clinical spectrum of pre-eclampsia ranges from mild to severe. In most cases, the progression is slow, and the disorder may never proceed beyond mild pre-eclampsia with few clinical signs apart from elevated blood pressure and proteinuria, with onset close to term. In other cases, the disease progresses more rapidly, from mild to severe within days or weeks, and may occur as early as the second trimester of pregnancy. Serious pre-eclampsia is an important cause of iatrogenic prematurity and an important cause of maternal deaths worldwide.
Classification
No universal agreement exists on the definition of pre-eclampsia. The National High Blood Pressure Education Program of the American College of Obstetrics and Gynecology recommends the following classification for the hypertensive disorders of pregnancy : chronic hypertension; pre-eclampsia–eclampsia; pre-eclampsia superimposed on chronic hypertension; gestational hypertension; transient hypertension of pregnancy in the absence of pre-eclampsia, with blood pressure returning to normal within 12 weeks postpartum.
The fact that pre-eclampsia is a syndrome has led to a certain heterogeneity in the diagnosis, and thus inconsistency in research reports. A variety of classification systems for pre-eclampsia has been applied by researchers, complicating the interpretation of results and making comparisons between studies difficult. The vast specter of clinical expressions and inconsistency in time of onset has prompted researchers to speculate whether pre-eclampsia is indeed several entities with different causes. Classifications that have been frequently used in the definition are mild, moderate and severe pre-eclampsia. More recently, the terms early onset (before 34 weeks) and late-onset (34 weeks or more) pre-eclampsia are more commonly used.
Early onset pre-eclampsia has been associated with signs of abnormal placentation, such as abnormal uterine artery Doppler measurements and fetal growth restriction, as well as adverse maternal outcomes. In contrast, late-onset pre-eclampsia is less likely to be related to abnormal placentation, and has been suggested to be determined by maternal factors.
Genetic studies implicate that susceptibility loci for the haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and for pre-eclampsia are located at different chromosomes, thus the HELLP syndrome may seem to be a distinct genetic and clinical entity, rather than a severe variant of pre-eclampsia.
Pre-eclampsia occurs in 5–8% of pregnancies worldwide, and is an important cause of maternal and fetal deaths. The prevalence of pre-eclampsia varies in different populations and in different ethnic groups.
Classification
No universal agreement exists on the definition of pre-eclampsia. The National High Blood Pressure Education Program of the American College of Obstetrics and Gynecology recommends the following classification for the hypertensive disorders of pregnancy : chronic hypertension; pre-eclampsia–eclampsia; pre-eclampsia superimposed on chronic hypertension; gestational hypertension; transient hypertension of pregnancy in the absence of pre-eclampsia, with blood pressure returning to normal within 12 weeks postpartum.
The fact that pre-eclampsia is a syndrome has led to a certain heterogeneity in the diagnosis, and thus inconsistency in research reports. A variety of classification systems for pre-eclampsia has been applied by researchers, complicating the interpretation of results and making comparisons between studies difficult. The vast specter of clinical expressions and inconsistency in time of onset has prompted researchers to speculate whether pre-eclampsia is indeed several entities with different causes. Classifications that have been frequently used in the definition are mild, moderate and severe pre-eclampsia. More recently, the terms early onset (before 34 weeks) and late-onset (34 weeks or more) pre-eclampsia are more commonly used.
Early onset pre-eclampsia has been associated with signs of abnormal placentation, such as abnormal uterine artery Doppler measurements and fetal growth restriction, as well as adverse maternal outcomes. In contrast, late-onset pre-eclampsia is less likely to be related to abnormal placentation, and has been suggested to be determined by maternal factors.
Genetic studies implicate that susceptibility loci for the haemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome and for pre-eclampsia are located at different chromosomes, thus the HELLP syndrome may seem to be a distinct genetic and clinical entity, rather than a severe variant of pre-eclampsia.
Pre-eclampsia occurs in 5–8% of pregnancies worldwide, and is an important cause of maternal and fetal deaths. The prevalence of pre-eclampsia varies in different populations and in different ethnic groups.
The role of the placenta
Successful implantation is the end result of complex molecular interactions between the hormonally primed uterus and a mature blastocyst. The trophoblast invasion has been described to serve attachment of the placenta to the uterus and transformation of spiral arteries into low-resistance vessels. However, the trophoblast cells invade the decidua and serve a variety of functions: communication with maternal immune cells, hormone and cytokine production, substitution of endothelial cells of maternal arterioles, angiogenesis, and fusion to giant cells.
About 2 weeks after fertilisation, extravillous trophoblast cells (EVT) start invasion into the maternal decidual stroma. EVT pass capillaries and glands of the uterine interstitium, before reaching the myometrium and spiral arteries. The spiral arteries are first invaded by intravasation of interstitial EVT, then they are blocked by cells that have passed the media of the vessels and have become endovascular trophoblasts. These plugs of cells remain until the end of the first trimester. Thus, maternal blood flow through the intervillous space of the placenta is not established until the beginning of the second trimester. Adequate invasion of the extravillous cytotrophoblasts into the maternal uterine spiral arteries is crucial in securing wide, low-resistance vascular channels, providing the developing fetus with a maximum blood flow.
The trophoblast invasion is less extensive in pre-eclamptic compared with normal pregnancies, and the transformation of the myometrial spiral arteries is inadequate even in the prescence of interstitial trophoblast invasion. This inadequacy results in reduced blood flow to the feto-placental unit, and may lead to poor fetal growth. Substances released from the ischaemic placenta are likely to trigger systemic endothelial dysfunction in the mother and thus the onset of the maternal symptoms of pre-eclampsia.
The maternal response
The maternal systemic disorder probably develops as a consequence of placental ischaemia. Ischaemia leads to the release of endothelial damaging factors to the maternal circulation. Syncytiotrophoblast debris, oxidised lipids, and anti-angiogenic factors, such as sFlt-l and soluble endoglin, have been suggested as damaging factors.
Pre-eclampsia is a multi-organ disease in the mother, and is characterised by generalised endothelial dysfunction and an exaggerated systemic inflammatory response. The severity of the disease seems to depend on maternal factors, pregnancy-specific factors or environmental factors.
Two major components are speculated to cause the exaggerated inflammatory response in women with pre-eclampsia; an excessive placental stimulus or an overactive maternal response to a normal placental stimulus. These two situations have been named ‘placental’ or ‘maternal’ pre-eclampsia. The two types may be mixed to varying degrees, and are thought to operate by the common mechanism of systemic inflammatory dysfunction. While placental pre-eclampsia is thought to represent a disorder that is specific to the pregnancy, maternal pre-eclampsia is specific to the woman and her predisposing factors.
The reduced placental perfusion in pre-eclampsia may cause a relative ischaemia. Circulating factors produced by a hypoxic placenta are proposed to cause endothelial dysfunction, and an excessive generation of reactive oxygen species (ROS). When in abundance, ROS can trigger a self-perpetuating chain reaction of chemical destruction involving cell lipids, DNA and proteins, leading to tissue degradation and cell death. Enzymatic and non-enzymatic antioxidant systems serve to protect against the harmful effects of ROS, and remove these highly reactive products. Oxidative stress is thus defined as disequilibrium between antioxidant defense and production of ROS species in favour of the latter. Examples of antioxidant enzymes are superoxide dismutase, glutathione reductase and catalase. Non-enzymatic antioxidants are vitamins C, E and A, glutathione and flavenoids. Pregnancy itself, in addition to being a condition of increased inflammatory responses, is characterised by evidence of increased oxidative stress. Oxidative stress has been shown in the placenta and in maternal peripheral blood cells
Angiogenic factors
Sufficient utero-placental blood flow is a key element in successful implantation and reproductive outcome, and increased attention has been devoted to altered angiogenesis in pre-eclampsia. Recent research has focused on angiogenic factors and their role in the development of pre-eclampsia. Decreased concentrations of circulating angiogenic factors, free placental growth factor and free vascular endothelial growth factor, have been reported in pregnant women with pre-eclampsia. Placental growth factor and vascular endothelial growth factor are necessary for normal endothelial function, and important factors in the angiogenesis of early placentation. Increased concentrations of the anti-angiogenic factors soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin are also reported. Soluble endoglin co-operates with sFlt-1 and induces endothelial dysfunction in vitro . In pregnant rats, a pre-eclampsia-like syndrome is induced.
Risk factors and causality
Although recognised since antiquity, current understanding of the causes of pre-eclampsia is still limited. Maternal, pre-conceptional and pregnancy-associated risk factors have been described, but pre-eclampsia is nevertheless ‘the disease of theories’. In 1694, Mauriceau set forth several aphorisms concerning eclampsia, including one which stated that primigravid women are at far greater risk of convulsions than are multiparas. In 1843, Johns confirmed the increased risk in primigravidas, and described an increased risk in women who had experienced convulsions in a previous pregnancy and in women that ‘were of full and plethoric habit’. In spite of extensive research on the field, these observations still stand as major risk factors and predictors of pre-eclampsia.
Consistent with the idea that pre-eclampsia may be maternal (mostly late onset), placental (mostly early onset) or mixed in origin, known risk factors for pre-eclampsia have been associated with maternal or pregnancy-specific characteristics, and may have different effects in the first compared with subsequent pregnancies. Paternal and environmental risk factors have also been suggested.
Established risk factors
Primiparity
Primiparous women are known to be at increased risk of pre-eclampsia, and pre-eclampsia is considered a condition of first pregnancy. In Norway, the prevalence in primiparous women according to the Medical Birth Registry of Norway (MBRN) is 5.1%. In a recent meta-analysis on the effects and mechanisms of primiparity on the risk of pre-eclampsia, 26 eligible studies reported a summary odds ratio for pre-eclampsia in primiparous compared with multiparous women of 2.42 (95% CI 2.16, 2.71). The range was 1.4 to 5.5. The increase in risk persisted after adjustment for confounders. Ødegård et al. reported similar estimates in a Norwegian case-control study. Immune maladaptation has been suggested as an explanation for effect of parity, but to date no studies have found evidence of such maladaptation. Recent research is increasingly focusing on angiogenic factors in the aetiology of pre-eclampsia. sFlt-1 is an inhibitor of placental growth factor and vascular endothelial growth factor, and is now accepted as a contributing factor in the pathophysiology of pre-eclampsia. Wolf et al. reported a decrease in circulating sFlt-1 from first to second pregnancy in analyses of the first two pregnancies of 97 women, suggesting that higher levels of sFlt-1 in primiparous women may predispose them to an elevated risk of pre-eclampsia.
Previous pre-eclampsia
In parous women, the crude risk of pre-eclampsia increases from 2.5% in women with one previous birth to 3.4% in women with more than five previous births (MBRN 1967–1998). A previous normal pregnancy is associated with a reduced risk of pre-eclampsia in a subsequent pregnancy, whereas previous pre-eclampsia is a strong risk factor for pre-eclampsia in multiparous women. The risk of recurrence is about 14%. The recurrence risk was reported even higher in a study based on hospital records, with a 20-fold increase in the pre-eclampsia risk compared with parous women with no previous pre-eclampsia. In a large review of risk factors for pre-eclampsia, Duckitt and Harrington reported a seven-fold increase in risk in women with previous pre-eclampsia compared with women with no previous pre-eclampsia. The recurrence risk was inversely related to gestational age at the first delivery. Mostello et al. recently reported an overall recurrence risk of 14.7%. However, for gestational ages less than 28 weeks in the first pregnancy, the risk was 38.6%; for gestational ages 29–32 years the risk was 29.1%; for gestational ages 33–36 years the risk was 21.9%; and finally the risk was 12.9% for gestational lengths 37 weeks or more. Women with recurrent pre-eclampsia are more likely to develop severe pre-eclampsia compared with nulliparous women, and they also have a higher risk of preterm deliveries, abruption of the placenta and fetal death caused by pre-clampsia. Thus, recurrent pre-eclampsia seems to reflect a more severe condition compared with first-time pre-eclampsia.
Maternal pre-pregnancy body mass index
A high body mass index (BMI) has consistently been found to increase pre-eclampsia risk, with reported odds ratios between 3 and 5 in obese (BMI > 30) compared with normal weight women. The higher risk seems to persist even after controlling for potential confounding factors such as age and chronic hypertension. It seems, however, that the increased risk associated with a high maternal BMI, is only true in mild or moderate pre-eclampsia (mostly late onset), and not with severe (early onset) pre-eclampsia. This finding is consistent with the idea that a high BMI is associated with an increased inflammatory response pushing the pregnancy into a pre-eclamptic state. Obesity is increasing in the developed world, affecting women of reproductive age and potentially complicating their pregnancies and deliveries. In Norway, the mean BMI for women increased from 22.9 in 1990 to 24.6 in 2001. The largest increase was seen in women aged 18–34 years. Consequently, the proportion of overweight women (BMI 25–29.9) increased from 20 to 27% in the same period and, for obesity (BMI ≥ 30), the proportion increased from 4 to 11%. Similar results have been reported from the USA. Accordingly, an increasing proportion of women developing hypertensive disorders of pregnancy can be expected.
Underlying medical conditions
Pre-existing medical conditions, some associated with endothelial damage, such as diabetes mellitus, antiphospholipid antibodies, autoimmune or renal disease, are associated with an increased risk of pre-eclampsia. For diabetes mellitus, incidence rates for pre-eclampsia range from 9–66% in women with pre-existing diabetic nephropathy. Chronic hypertension is an important risk factor for the development of superimposed pre-eclampsia. A family history of hypertension is also associated with an increased risk, and so is a systolic blood pressure in the upper normal range as measured in early pregnancy.
Smoking in pregnancy
Smoking in pregnancy has repeatedly been associated with a reduced risk of pre-eclampsia in primiparous and multiparous women, singleton and multifetal pregnancies and for mild and severe pre-eclampsia. Typically, the relative risk is about 0.5 to 0.8 compared with non-smokers. Although smoking reduces the incidence, it is associated with an unfavourable fetal outcome in pregnancies complicated by pre-eclampsia. This finding was recently confirmed by Pipkin, who also found that women with pre-eclampsia who had stopped smoking while pregnant had better outcomes than women who continued to smoke (i.e. gestational age at delivery, onset of pre-eclampsia and birth weight). Others have found that women who smoke but quit before they become pregnant, or in early pregnancy, do not seem to have a reduced risk of pre-eclampsia. Thus, the evidence on the effect of smoking cessation on pre-eclampsia risk is still conflicting, and the mechanisms behind the effect of cigarette smoking on pre-eclampsia risk are unknown.
The prevalence of smoking during pregnancy is decreasing in many developed countries. This is true also in Norway. Information on smoking habits was unavailable in the MBRN up until 1999, but the prevalence of women reporting smoking in early pregnancy in Norway by year of birth, as reported to the MBRN, has decreased from more than 25% in 1999 to about 16% in 2006. By the time of birth, the overall prevalence of women reporting smoking was decreased by 7%.
Pregnancy-specific factors
Multiple gestations are consistently associated with an increased risk of pre-eclampsia. The risk is two to three times higher in a twin pregnancy compared with a singleton pregnancy. The incidence of hypertensive disorders is also higher among primiparous twin mothers than among multiparous twin mothers. We compared recurrence risks of preeclampsia in twin and singleton pregnancies among 550218 women in the Medical Birth Registry of Norway, 1967-1998. The recurrence risk of preeclampsia in second pregnancy for women with a singleton pregnancy with preeclampsia the first time was 14.1% (95% CI: 13.6-14.6). For women with a first time twin pregnancy the recurrence risk was lower, 6.8% (CI: 4.3-10.1). This observation is consistent with a polygenic liability model for preeclampsia. Pre-eclampsia may also occur in hydatidiform moles, which should be suspected if pre-eclampsia occurs before 20 weeks gestation. Twin and molar pregnancies are both associated with an increased placental mass. The observed increase in risk is consequently believed to be associated with an increased release of placental debris, inducing an excess systemic inflammatory response in the mother, lowering her threshold for developing pre-eclampsia. Recently, a higher level of sFlt-1 (an anti-angiogenic factor) in twin compared with singleton pregnancies has been found, supporting such hypothesis. An alternative explanation may be an increased risk caused by the increased paternal genetic contribution in both conditions. Assisted reproductive treatment has also been associated with an increased risk of pre-eclampsia, both infertility treatment per se , and treatment with donated gametes.
Ethnicity
Among nulliparous women, black women have a risk of pre-eclampsia that is twice as high as that of white women. They are also more likely to have hypertension that is independent of pregnancy. Similar results were reported by Dempsey et al., who also found the risk in African–American women to be higher than the risk in white or Hispanic women, and by Knuist et al., who found black women to have a doubled risk compared with white women. Women of other ethnic origins (Mediterranean, Asian or other) also had higher risks, but the numbers were small, and the estimates did not reach significance.
Unresolved risk factors
Maternal age
Extremes of maternal age have been associated with an increased risk of pre-eclampsia in some, but not all studies. In a review of risk factors for pre-eclampsia at ante-natal booking, including 52 cohort and case-control studies, women older than 40 years of age had almost twice the risk of developing pre-eclampsia compared with younger women. The increased risk was similar in primiparous and multiparous women. Young maternal age was not associated with an increased risk of pre-eclampsia, whichever cut off age was used. None of the studies had controlled for pre-existing chronic disease, such as hypertension or diabetes. Nationwide US data suggest that the risk of pre-eclampsia increases by 30% for every additional of age past 34 years. Other studies have been unable to show any effect of maternal age.
Previous miscarriages and induced abortions
Studies on the effect of previous miscarriages on the risk of pre-eclampsia have shown conflicting results. A small number of studies have examined the effect of previous miscarriages or preterm births on pre-eclampsia risk. Unfortunately, the studies have been inconsistent in their results. Campbell et al. studied a population of 29,851 pregnant women from Aberdeen between 1967 and 1978. The incidence of pre-eclampsia in the second pregnancy of women whose first pregnancy had ended in early miscarriage (less than 13 weeks) was similar to the population incidence in a first pregnancy. After a late miscarriage, however, the risk of pre-eclampsia in a subsequent pregnancy was significantly reduced. After adjusting for confounding factors, Seidman et al. also found a protective effect of a prior induced abortion, but not following a miscarriage. The study population consisted of 9771 women pregnant for the first or second time. In 1997, Sibai et al. assessed risk factors for pre-eclampsia in 4589 healthy nulliparous women participating in the Calcium for Preeclampsia Prevention study. After adjusting for a number of potential confounding variables, a history of induced abortion or miscarriage offered no protection against pre-eclampsia in a subsequent pregnancy, however, no separate analyses were performed for the two entities.
In a large population-based retrospective cohort study in Canada, no significant difference was found in incidence of pre-eclampsia in nulliparous women who had undergone a prior abortion (2.6 %) compared with nulliparous women who had not undergone a prior abortion (2.9 %; adjusted odds ratio [aOR] 0.89, 95% CI 0.78 to 1.01). In multiple regression analysis, however, one single prior abortion was associated with a slightly decreased risk of pre-eclampsia (aOR 0.84; 95% CI 0.72 to 0.97). The incidence of pre-eclampsia in women with one prior preterm birth was similar to the incidence in primigravid women (2.9 % and 2.8 %). We have studied the effect of previous induced abortions and recurrent miscarriages in 20,846 primiparous women participating in the Norwegian Mother and Child Cohort Study. We found that two or more induced abortions reduced the risk of pre-eclampsia significantly (OR 0.36; 95% CI 0.18 to 0.73). Adjustment for confounders, including change in paternity, did not change the estimates.
Spontaneous miscarriages may, to a larger extent than induced abortions, be associated with other factors, such as infertility, which can increase the risk of pre-eclampsia. Many of the previous studies have not separated spontaneous miscarriages from elective terminations, which, from a pathophysiologic point of view, are totally different entities. Thus, in the same dataset, we studied the risk of pre-eclampsia in women reporting recurrent spontaneous miscarriages. A small fraction of all women (0.6%) reported three or more consecutive spontaneous miscarriages. A threefold increase in risk of pre-eclampsia was seen in women reporting both recurrent spontaneous abortions and infertility treatment, compared with women with one previous spontaneous abortion without infertility treatment (aOR 3.46; 95% CI 1.49, 8.03). The increase in risk was restricted to women with no change in paternity. These results are compatible with previous reports on feto–maternal genetic mismatch as a possible cause of pre-eclampsia, and support the idea that subfecundity, recurrent spontaneous abortion of otherwise unknown causes and pre-eclampsia share elements of the same pathophysiology.
Inter-pregnancy interval and primipaternity
In 1996, Adams et al. reported associations between paternity, inter-pregnancy interval and pre-eclampsia. Their analysis included 139,085 women from Georgia between 1980 and 1992, whose first and second pregnancies ended in singleton live births and for whom the fathers were identified. The rate of pre-eclampsia was 4.7% in the first pregnancy and 1.4% in the second pregnancy. Among women who did not have pre-eclampsia in the first pregnancy, the rate of pre-eclampsia in the second pregnancy was 1.0% when the father was the same and 1.4% when the father changed between pregnancies. Among the women with pre-eclampsia in the first pregnancy ( n = 6521), the rate of pre-eclampsia in the second pregnancy was 10.0% when the father was the same, and 8.9% when the father changed between pregnancies. However, in multivariate logistic regression analyses controlling for inter-pregnancy interval, year of birth, maternal age and race, non-significant odds ratios near unity for a change in paternity was found, regardless of whether there was a history of pre-eclampsia in the first pregnancy or not.
Wi and Li found no effect of the interval between deliveries but, for women with a change in paternity, a 30% increase in pre-eclampsia risk in women with no previous pre-eclampsia was reported. We, along with others, have found increased risk of pre-eclampsia with intervals longer than 4–5 years. The risk increased with increasing interval for all women, regardless of change in paternity between pregnancies ( Table 1 ).
| Interval between pregnancies (years) | Same paternity | New paternity | ||
|---|---|---|---|---|
| N | % | N | % | |
| ≤ 1 | 53 out of 4648 | 1.1 | 108 | 0 |
| 1–5 | 4102 out of 377,046 | 1.1 | 72 out of 873 | 0.8 |
| 6–10 | 1062 out of 49518 | 2.1 | 192 out of 11,875 | 1.6 |
| 11–15 | 78 out of 2502 | 3.1 | 61 out of 2752 | 2.2 |
| > 15 | 34 out of 755 | 4.5 | 48 out of 1572 | 3.1 |
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