Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies

Methods

We searched Medline (1966 to July 2002) and Embase (1974 to July 2002) for publications in any language that considered the association between identified risk factors detectable at an antenatal booking visit (box 1) and the subsequent development of pre-eclampsia. A multidisciplinary guideline group set up to formulate evidence based guidelines on the community screening and detection of pre-eclampsia identified the risk factors. Our search terms included pre-eclampsia, preeclampsia, eclampsia, toxaemia, toxemia, meta-analysis, systematic review, risk factors, risk, causality, cohort studies, case-control studies. We also studied reference lists of published letters and classic review articles and asked experts in the field.

We initially selected studies with a cohort or case-control design that included pre-eclampsia (either as an outcome or to define cases) and the risk factors of interest. We assessed the quality of these studies with a checklist, adapted from Taggart et al,6 using participant selection, comparability of groups at baseline, and how the diagnosis of pre-eclampsia was made and according to what definition (box 2). We excluded any study that did not score in any category. We used study size, and the prospective or retrospective design of cohort studies, to score for heterogeneity. We independently extracted data from the included studies and resolved any differences by discussion.

Where data were available, we calculated the unadjusted relative risk with 95% confidence intervals for each study and across studies using the random effects model with the MetaView statistical package (MetaView 4.01, Update Software, Oxford). We calculated the I²> statistic7 for combined studies. This estimates the proportion of total variation in study estimates that is due to heterogeneity and, unlike χ²>, does not depend on the number of included studies. For some risk factors, we could not combine data from the included studies. We have described the results from these studies narratively and presented the published adjusted odds ratios or relative risks separately.

Age

All except one study, which looked at women aged ≥ 40, failed to control or address differences at baseline (particularly pre-existing chronic disease such as hypertension or diabetes). Women aged ≥ 40 had approaching twice the risk of developing pre-eclampsia, whether they were primiparous or multiparous (relative risk 1.68, 95% confidence interval 1.23 to 2.29, and 1.96, 1.34 to 2.87, respectively).8 Nationwide US data suggest that the risk of pre-eclampsia increases by 30% for every additional year of age past 34.9 Young maternal age did not seem to affect the risk of developing pre-eclampsia, whichever cut off age was used.

Parity

Nulliparity almost triples the risk for pre-eclampsia (2.91, 1.28 to 6.61) (three cohort studies10^–12); this is supported by adjusted odds ratios for nulliparity from two other cohort studies.13 14 Women with pre-eclampsia are twice as likely to be nulliparous as women without pre-eclampsia (2.35, 1.80 to 3.06) (six case-control studies10 15^–19).

Previous pre-eclampsia

Women who have pre-eclampsia in a first pregnancy have seven times the risk of pre-eclampsia in a second pregnancy (7.19, 5.85 to 8.83) (five cohort studies12 20^–23). Women with pre-eclampsia in their second pregnancy are also more than seven times more likely to have a history of pre-eclampsia in their first pregnancy than women in their second pregnancy who do not develop pre-eclampsia (7.61, 4.3 to 13.47) (seven case-control studies15 16 18 19 24^–26).

Family history of pre-eclampsia

A family history of pre-eclampsia nearly triples the risk of pre-eclampsia (2.90, 1.70 to 4.93) (two cohort studies27 28). Women with severe pre-eclamptic toxaemia are more likely to have a mother rather than a mother in law who had had pre-eclampsia.29

Multiple pregnancy

When a woman is pregnant with twins her risk of pre-eclampsia nearly triples (five cohort studies, 2.93, 2.04 to 4.21).10 12 18 30 31 Neither the chorionicity nor zygosity of the pregnancies alters this increased risk (data not shown32 33). One study found that a triplet pregnancy nearly triples the risk of pre-eclampsia compared with a twin pregnancy (2.83, 1.25 to 6.40).34

Pre-existing medical conditions

Insulin dependent diabetes—The likelihood of pre-eclampsia nearly quadruples if diabetes is present before pregnancy (3.56, 2.54 to 4.99) (three cohort studies12 31 35).

Pre-existing hypertension—In a population based nested case-control study, Davies et al found that the prevalence of chronic hypertension was higher in women who developed pre-eclampsia than women who did not (12.1% v 0.3%).25 McCowan et al compared outcomes in 129 women with chronic hypertension who did not develop superimposed pre-eclampsia with 26 women with chronic hypertension who did.36 Those with superimposed pre-eclampsia had significantly higher rates of perinatal morbidity (odds ratio 8.8, 2.6 to 39.0), small for gestational age infants (5.6, 1.8 to 16.0), and delivery before 32 weeks (15.0, 5.7 to 38.0). A diastolic blood pressure before 20 weeks of either ≥ 110 mm Hg (5.2, 1.5 to 17.2) or ≥ 100 mm Hg (3.2, 1.0 to 7.8) is most predictive of the development of superimposed pre-eclampsia.

Renal disease—Davies et al also found that the prevalence of renal disease was higher in women who developed pre-eclampsia compared with those that did not (5.3% v 1.8%).25 Only one study compared women with renal disease, due to a history of urinary tract infections, with a prospective control population matched for age, parity, smoking, and date of delivery.37 In 69 continuing pregnancies, 6.7% (2/30) of the women who had urinary tract infections developed pre-eclampsia (both primigravida with scarred kidneys) compared with 2.6% (1/39) of women in the control group.

Chronic autoimmune disease—In a matched case-control study Stamilio et al found that women who developed pre-eclampsia were more likely to have an autoimmune disease (relative risk 6.9, 1.1 to 42.3).19

Antiphospholipid syndrome—The presence of antiphospholipid antibodies (anticardiolipin antibodies or lupus anticoagulant or both) significantly increases the risk of developing pre-eclampsia (9.72, 4.34 to 21.75) (two cohort studies38 39). However, when women who developed pre-eclampsia were matched with women who did not, they were no more likely to be positive for lupus anticoagulant or anticardiolipin antibodies (6.12, 0.35 to 108.35) (three case-control studies40 41 42).

Time between pregnancies

In a Norwegian population study Skjaerven et al studied 551 478 women who had two or more singleton deliveries and 209 423 women who had three or more singleton deliveries.43 The association between risk of pre-eclampsia and interval was more significant than the association between risk and change of partner. The risk in a second or third pregnancy was directly related to the time elapsed since the previous delivery. When the interval was 10 years or more the risk of pre-eclampsia was about the same as that in nulliparous women. After adjustment for the presence or absence of a change of partner, maternal age, and year of delivery, the probability of pre-eclampsia was increased by 1.12 for each year increase in the interval (odds ratio 1.12, 1.11 to 1.13).

A cross sectional study from Uruguay found that women with more than 59 months between pregnancies had significantly increased risks of pre-eclampsia (relative risk 1.83, 1.72 to 1.94) compared with women with intervals of 18-23 months.44

A Danish cohort study found that a long interval between pregnancies was associated with a significantly higher risk of pre-eclampsia in a second pregnancy when pre-eclampsia had not been present in the first pregnancy and paternity had not changed.45

Body mass index

Although the studies that looked at body mass index before pregnancy all used different ranges, they all showed effects in the same direction, suggesting an overall doubling of risk of pre-eclampsia with a raised body mass index (2.47, 1.66 to 3.67) (six studies12 16 31 46^–48). One cohort study showed that women with a body mass index > 35 before pregnancy had over four times the risk of pre-eclampsia compared with women with a pre-pregnancy body mass index of 19-27 (4.39, 3.52, 5.49).46 We combined all studies that looked at raised compared with normal body mass index at booking and found that the risk of pre-eclampsia is increased by 50%.49^–51 Notably, a body mass index > 35 at booking doubles the pre-eclampsia risk (one cohort study, 2.12, 1.56 to 2.88).49 Confounding factors can affect the relation between body mass index and pre-eclampsia as women with raised body mass index may be older and more at risk of chronic hypertension. However, published odds ratios that have been adjusted to take some of these factors into account still suggest an increased risk with a raised body mass index (see table 2). A study comparing low and normal body mass index at booking found that the risk of pre-eclampsia was significantly reduced with a body mass index < 20 (odds ratio 0.76, 0.62 to 0.92, adjusted for diabetes and smoking).52

Blood pressure at booking

Reiss et al matched 30 women with pre-eclampsia for age, race, and parity with normotensive control women.53 Both systolic and diastolic blood pressures were significantly higher in the first tri-mester for women who later developed pre-eclampsia. The study did not define cut off values.

Sibai et al found that higher systolic and diastolic blood pressures at the first visit were associated with an increased incidence of pre-eclampsia (3.8% in women with diastolic blood pressure of < 55 mm Hg, 7.4% in those with diastolic blood pressure 70-84 mm Hg).54 However, their recruitment was limited to women with a first blood pressure reading of ≤ 135/85 mm Hg.

In a population based nested case-control study Odegard et al found that a systolic blood pressure ≥ 130 mm Hg compared with < 110 mm Hg at the first visit before 18 weeks was significantly associated with the development of pre-eclampsia later in pregnancy (adjusted odds ratio 3.6, 2.0 to 6.6).18 The association with a diastolic pressure ≥ 80 mm Hg compared with < 60 mm Hg was similar but not significant (1.8, 0.7 to 4.6).

In a case-control study Stamilio et al found that a mean arterial pressure > 90 mm Hg at the first prenatal visit was significantly associated with the development of severe pre-eclamptic toxaemia (relative risk 3.7, 2.1 to 6.6).19

Confirmed proteinuria at booking

We did not find any studies with an appropriate control group that examined the incidence of pre-eclampsia in women who have proteinuria at booking but no previously known renal disease.