Risk factors for pre-eclampsia at antenatal booking: systematic review
http://www.100md.com
《英国医生杂志》
Kirsten Duckitt, consultant obstetrician1, Deborah Harrington, subspecialty trainee in maternal and fetal medicine1
1 Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Oxford OX3 9DU
Correspondence to: K Duckitt Kduckitt@doctors.org.uk
We identified over 1000 studies, and, after screening s, we read 149 papers. We excluded 34 because they were observational studies with no reference group or review articles, nine that reported eclampsia alone or did not separate out preeclampsia from pregnancy induced hypertension, 26 that did not concern the relevant risk factors, and 28 because they scored no points in one or more categories in the quality assessment. Fifty two studies (13 prospective cohort studies, 25 retrospective cohort studies, and 14 case-control studies) were therefore included in the systematic review. Of these, 23 had fewer than 100 participants in at least one of the groups. Table 1 shows details of the quality scores. A list of excluded studies is available on request.
Table 1 Quality assessment of included studies (points scored, see box 2)
Box 2 Quality assessment of non-randomised studies (points scored)
Participant selection
Cohort studies
Selected cohort was representative of the general pregnant population (1)
Cohort was a selected group or the selection of the group was not described (0)
Case-control studies
Cases and controls drawn from the same population (1)
Cases and controls drawn from different sources or the selection of groups was not described (0)
Comparability of groups
No differences between the groups explicitly reported (especially in terms of age, parity, pre-existing medical disease, singleton pregnancy) unless it was one of these variables that was under investigation, or such differences were adjusted for (2)
Differences between groups were not recorded (1)
Groups differed (0)
Outcomes
Definition of pre-eclampsia
Referenced definition (2)
Explicit definition that included new onset hypertension after 20 weeks' gestation with new proteinuria (1)
Pre-eclampsia not defined or unacceptable definition (0)
How the diagnosis of pre-eclampsia was made
Review of notes or prospective assignment (2)
ICD or database coding (1)
Process was not described (0)
Size
> 100 participants in each group (2)
< 100 participants in each group (1)
Cohort design
Prospective cohort design (2)
Retrospective design (1)
As expected, there was more evidence of heterogeneity, as assessed by the I2 statistic, in the case-control studies than in the cohort studies. The available published adjusted odds ratios or relative risks, however, were similar to the unadjusted relative risks calculated in the meta-analysis.
Tables 2 and 3 summarise the results by risk factor. We found no data of sufficient quality on the presence of proteinuria at booking. There were also no data to calculate unadjusted relative risks for interval between births, existing hypertension, or existing renal disease. Published adjusted relative risks were available for the interval between births (table 3).
Table 2 Published and calculated relative risks and odds ratios for cohort studies
Table 3 Case control studies: pre-eclampsia
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.
Discussion
Confidential Enquiries into Maternal Deaths. Why mothers die 1997-1999. The fifth report of the confidential enquiries into maternal deaths in the United Kingdom. London: Royal College of Obstetricians and Gynaecologists Press, 2001.
Confidential Enquiry into Stillbirths and Deaths in Infancy. 8th annual report. London: Maternal and Child Health Research Consortium, 2001.
World Health Organization International Collaborative Study of Hypertensive Disorders of Pregnancy. Geographic variation in the incidence of hypertension in pregnancy. Am J Obst Gynecol 1988;158: 80-3.
Conde-Agudelo A, Althabe F, Belizan JM, Kafury-Goeta AC. Cigarette smoking during pregnancy and risk of pre-eclampsia: a systematic review. Am J Obstet Gynecol 1999;181: 1026-35.
National Institute for Clinical Excellence. NICE Guideline CG6 Antenatal care—routine care for the healthy pregnant woman. London: NICE, 2003.
Taggart DP, D'Amico R, Altman DG. Effect of arterial revascularisation on survival: a systematic review of studies comparing bilateral and single internal mammary arteries. Lancet 2001;358: 870-5.
Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21: 1539-58.
Bianco A, Stone J, Lynch L, Lapinski R, Berkowitz G, Berkowitz RL. Pregnancy outcome at age 40 and older. Obstet Gynecol 1996;87: 917-22.
Saftlas AF, Olson DR, Franks Al, Atrash HK, Pokras R. Epidemiology of preeclampsia and eclampsia in the United states, 1979-1986. Am J Obstet Gynecol 1990;163: 460-5.
Coonrod DV, Hickok DE, Zhu K, Easterling TR, Daling JR. Risk factors for preeclampsia in twin pregnancies: a population-based cohort study. Obstet Gynecol 1995;85: 645-50.
Lawoyin TO, Ani F. Epidemiologic aspects of pre-eclampsia in Saudi Arabia. East Afr Med J 1996;73: 404-6.
Lee CJ, Hsieh TT, Chiu TH, Chen KC, Lo LM, Hung TH. Risk factors for pre-eclampsia in an Asian population. Int J Gynecol Obstet 2000;70: 327-33.
Khan KS, Daya S. Plasma glucose and pre-eclampsia. Int J Gynecol Obstet 1996;53: 111-6.
Hartikainen A, Aliharmi RH, Rantakallio PT. A cohort study of epidemiological associations and outcomes of pregnancies with hypertensive disorders. Hypertens Pregnancy 1998;17: 31-41.
Eskenazi B, Fenster L, Sidney SA. Multivariate analysis of risk factors for preeclampsia. JAMA 1991;266: 237-41.
Stone JL, Lockwood CJ, Berkowitz GS, Alvarez M, Lapinski R, Berkowitz RL. Risk factors for severe preeclampsia. Obstet Gynecol 1994;83: 357-61.
Chen CL, Cheng Y, Wang PH, Juang CM, Chiu LM, Yang MJ, et al. Review of pre-eclampsia in Taiwan: a multi-institutional study. Zhonghua Yi Xue Za Zhi (Taipei) 2000;63: 869-75.
Odegard RA, Vatten LJ, Nilsen ST, Salvesen KA, Austgulen R. Risk factors and clinical manifestations of pre-eclampsia. Br J Obstet Gynaecol 2000;107: 1410-6.
Stamilio DM, Sehdev HM, Morgan MA, Propert K, Macones GA. Can antenatal clinical and biochemical markers predict the development of severe preeclampsia? Am J Obstet Gynecol 2000;182: 589-94.
Campbell DM, MacGillivray I, Carr-Hill R. Pre-eclampsia in second pregnancy. Br J Obstet Gynaecol 1985;92: 131-40.
Sibai BM, El Nazer A, Gonzalez-Ruiz A. Severe preeclampsia-eclampsia in young primigravid women: subsequent pregnancy outcome and remote prognosis. Am J Obstet Gynecol 1986;155: 1011-6.
Makkonen N, Heinonen S, Kirkinen P. Obstetric prognosis in second pregnancy after preeclampsia in first pregnancy. Hypertens Pregnancy 2000;19: 173-81.
Dukler D, Porath A, Bashiri A, Erez O, Mazor M. Remote prognosis of primiparous women with preeclampsia. Eur J Obstet Gynecol Reprod Biol 2001;96: 69-74.
Moore MP, Redman CW. Case-control study of severe pre-eclampsia of early onset. BMJ 1983;287: 580-3.
Davies AM, Czaczkes JW, Sadovsky E, Prywes R, Weiskopf P, SterkVV. Toxemia of pregnancy in Jerusalem I. Epidemiological studies of a total community. Isr J Med Sci 1970;6: 253-66.
Banias BB, Devoe LD, Nolan TE. Severe preeclampsia in preterm pregnancy between 26 and 32 weeks' gestation. Am J Perinatol 1992;9: 357-60.
Arngrimsson R, Bjornsson S, Geirsson RT, Bjornsson H, Walker JJ, Snaedal G. Genetic and familial predisposition to eclampsia and pre-eclampsia in a defined population. Br J Obstet Gynaecol 1990;97: 762-9.
Cincotta RB, Brennecke SP. Family history of pre-eclampsia as a predictor for pre-eclampsia in primigravidas. Int J Gynaecol Obstet 1998;60: 23-7.
Sutherland A, Cooper DW, Howie PW, Liston WA, MacGillivray I. The incidence of severe pre-eclampsia amongst mothers and mothers-in-law of pre-eclamptics and controls. Br J Obstet Gynaecol 1981;88: 785-91.
Santema JG, Koppelaar I, Wallenburg HC. Hypertensive disorders in twin pregnancy. Eur J Obstet Gynecol Reprod Biol 1995;58: 9-13.
Ros HS, Cnattingius S, Lipworth L. Comparison of risk factors for preeclampsia and gestational hypertension in a population-based cohort study. Am J Epidemiol 1998;147;11(suppl): 1062-70.
Maxwell CV, Lieberman E, Norton M, Cohen A, Seely EW, Lee-Parritz A. Relationship of twin zygosity and risk of preeclampsia. Am J Obstet Gynecol 2001;185: 819-21.
Savvidou MD, Karanastasi E, Skentou C, Geerts L, Nicolaides KH. Twin chorionicity and pre-eclampsia. Ultrasound Obstet Gynecol 2001;18: 228-31.
Skupski DW, Nelson S, Kowalik A, Polaneczky M, Smith-Levitin M, Hutson JM, Rosenwaks Z. Multiple gestations from in vitro-fertilization: Successful implantation alone is not associated with subsequent pre-eclampsia. Am J Obstet Gynecol 1996;175: 1029-32.
Garner PR, D'Alton ME, Dudley DK, Huard P, Hardie M. Preeclampsia in diabetic pregnancies. Am J Obstet Gynecol 1990;163: 505-8.
McCowan LM, Buist RG, North RA, Gamble G. Perinatal morbidity in chronic hypertension. Br J Obstet Gynaecol 1996;103: 123-9.
Martinell J, Jodal U, Lidin-Janson G. Pregnancies in women with and without renal scarring after urinary infections in childhood. BMJ 1990;300: 840-4.
Pattison NS, Chamley LW, McKay EJ, Liggins GC, Butler WS. Antiphospholipid antibodies in pregnancy: prevalence and clinical associations. Br J Obstet Gynaecol 1993;100: 909-13.
Yasuda M, Takakuwa K, Tokunaga A, Tanaka K. Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy. Obstet Gynecol 1995;86: 555-9.
Branch DW, Andres R, Digre KB, Rote NS, Scott JR. The association of antiphospholipid antibodies with severe preeclampsia. Obstet Gynecol 1989;73: 541-5.
Sletnes KE, Wisloff F, Moe N, Dale PO. Antiphospholipid antibodies in pre-eclamptic women: relation to growth retardation and neonatal outcome. Acta Obstet Gynecol Scand 1992;71: 112-7.
Dreyfus M, Hedelin G, Kutnahorsky R, Lehmann M, Vivelle B, Langer B, et al. Antiphospholipid antibodies and preeclampsia: a case-control study. Obstet Gynecol 2001;97: 29-34.
Skjaerven R, Wilcox AJ, Lie RT. The interval between pregnancies and the risk of preeclampsia. N Engl J Med 2002;346: 33-8.
Conde-Agudelo A, Belizan JM. Maternal morbidity and mortality associated with interpregnancy interval: cross sectional study. BMJ 2000;321: 1255-9.
Basso O, Christensen K, Olsen J. Higher risk of pre-eclampsia after change of partner. An effect of longer interpregnancy intervals? Epidemiology 2001;12: 624-9.
Bianco AT, Smilen SW, Davis Y, Lopez S, Lapinski R, Lockwood CJ. Pregnancy outcome and weight gain recommendations for the morbidly obese woman. Obstet Gynecol 1998;91: 97-102.
Fields SJ, Vainder M, Livshits G, Merlob P, Sirotta L. Obesity and the risk of toxaemia of pregnancy. Ann Hum Biol 1996;23: 353-62.
Thadhani R, Stampfer MJ, Hynter DJ, Manson JE, Solomon CG, Curhan GC. High body mass index and hypercholesterolaemia: risk of hypertensive disorders of pregnancy. Obstet Gynecol 1999;94: 543-50.
Sibai BM, Ewell M, Levine RJ, Klebanoff MA, Esterlitz J, Catalano PM, et al. Risk factors associated with preeclampsia in healthy nulliparous women. The Calcium for Preeclampsia Prevention (CPEP) Study Group. Am J Obstet Gynecol 1997;177: 1003-10.
Bowers D, Cohen WR. Obesity and related pregnancy complications in an inner-city clinic. J Perinatol 1999;19: 216-9.
Van Hoorn J, Dekker G, Jeffries B. Gestational diabetes versus obesity as risk factors for pregnancy-induced hypertensive disorders and fetal macrosomia. Aust N Z J Obstet Gynaecol 2002;42: 29-34.
Sebire NJ, Harris J, Regan L, Robinson S. Is maternal underweight really a risk factor for adverse pregnancy outcome? A population-based study in London. Br J Obstet Gynaecol 2001;108: 61-6.
Reiss RE, O'Shaughnessy RW, Quilligan TJ, Zuspan FP. Retrospective comparison of blood pressure course during preeclamptic and matched control pregnancies. Am J Obstet Gynecol 1987;156: 894-8.
Sibai BM, Gordon T, Thom E, Caritis SN, Klebanoff M, McNellis D, et al. Risk factors for preeclampsia in healthy nulliparous women: a prospective multicenter study. Am J Obstet Gynecol 1995;172: 642-8.
Sattar N, Clark P, Holmes A, Lean MEJ, Walker I, Greer IA. Antenatal waist circumference and hypertension risk. Obstet Gynecol 2001;97: 268-71.
Bradford JA, Giles WB. Teenage pregnancy in western Sydney. Aust N Z J Obstet Gynaecol 1989;29: 1-4.
Brown HL, Fan YD, Gonsoulin WJ. Obstetric complications in young teenagers. S Med J 1964;84: 46-8.
Konje JC, Palmer A, Watson A, Hay DM, Imrie A, Ewings P. Early teenage pregnancies in Hull. Br J Obstet Gynaecol 1992;99: 969-73.
Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet 1991;337: 867-72.
Chalmers TC, Levin H, Sacks HS. Meta-analysis of clinical trials as a scientific discipline. I: control of bias and comparison with large co-operative trials. Stat Med 1987;6: 315-25.
Mattar F, Sibai BM. Eclampsia. VIII. Risk factors for maternal morbidity. Am J Obstet Gynecol 2000;182: 307-12.
Milne F, Redman C, Walker J, Baker P, Bradley J, Cooper C, et al. The pre-eclampsia community guideline (PRECOG): how to screen for and detect onset of pre-eclampsia in the community. BMJ 2005 (in press).(Kirsten Duckitt)
1 Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Oxford OX3 9DU
Correspondence to: K Duckitt Kduckitt@doctors.org.uk
We identified over 1000 studies, and, after screening s, we read 149 papers. We excluded 34 because they were observational studies with no reference group or review articles, nine that reported eclampsia alone or did not separate out preeclampsia from pregnancy induced hypertension, 26 that did not concern the relevant risk factors, and 28 because they scored no points in one or more categories in the quality assessment. Fifty two studies (13 prospective cohort studies, 25 retrospective cohort studies, and 14 case-control studies) were therefore included in the systematic review. Of these, 23 had fewer than 100 participants in at least one of the groups. Table 1 shows details of the quality scores. A list of excluded studies is available on request.
Table 1 Quality assessment of included studies (points scored, see box 2)
Box 2 Quality assessment of non-randomised studies (points scored)
Participant selection
Cohort studies
Selected cohort was representative of the general pregnant population (1)
Cohort was a selected group or the selection of the group was not described (0)
Case-control studies
Cases and controls drawn from the same population (1)
Cases and controls drawn from different sources or the selection of groups was not described (0)
Comparability of groups
No differences between the groups explicitly reported (especially in terms of age, parity, pre-existing medical disease, singleton pregnancy) unless it was one of these variables that was under investigation, or such differences were adjusted for (2)
Differences between groups were not recorded (1)
Groups differed (0)
Outcomes
Definition of pre-eclampsia
Referenced definition (2)
Explicit definition that included new onset hypertension after 20 weeks' gestation with new proteinuria (1)
Pre-eclampsia not defined or unacceptable definition (0)
How the diagnosis of pre-eclampsia was made
Review of notes or prospective assignment (2)
ICD or database coding (1)
Process was not described (0)
Size
> 100 participants in each group (2)
< 100 participants in each group (1)
Cohort design
Prospective cohort design (2)
Retrospective design (1)
As expected, there was more evidence of heterogeneity, as assessed by the I2 statistic, in the case-control studies than in the cohort studies. The available published adjusted odds ratios or relative risks, however, were similar to the unadjusted relative risks calculated in the meta-analysis.
Tables 2 and 3 summarise the results by risk factor. We found no data of sufficient quality on the presence of proteinuria at booking. There were also no data to calculate unadjusted relative risks for interval between births, existing hypertension, or existing renal disease. Published adjusted relative risks were available for the interval between births (table 3).
Table 2 Published and calculated relative risks and odds ratios for cohort studies
Table 3 Case control studies: pre-eclampsia
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.
Discussion
Confidential Enquiries into Maternal Deaths. Why mothers die 1997-1999. The fifth report of the confidential enquiries into maternal deaths in the United Kingdom. London: Royal College of Obstetricians and Gynaecologists Press, 2001.
Confidential Enquiry into Stillbirths and Deaths in Infancy. 8th annual report. London: Maternal and Child Health Research Consortium, 2001.
World Health Organization International Collaborative Study of Hypertensive Disorders of Pregnancy. Geographic variation in the incidence of hypertension in pregnancy. Am J Obst Gynecol 1988;158: 80-3.
Conde-Agudelo A, Althabe F, Belizan JM, Kafury-Goeta AC. Cigarette smoking during pregnancy and risk of pre-eclampsia: a systematic review. Am J Obstet Gynecol 1999;181: 1026-35.
National Institute for Clinical Excellence. NICE Guideline CG6 Antenatal care—routine care for the healthy pregnant woman. London: NICE, 2003.
Taggart DP, D'Amico R, Altman DG. Effect of arterial revascularisation on survival: a systematic review of studies comparing bilateral and single internal mammary arteries. Lancet 2001;358: 870-5.
Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21: 1539-58.
Bianco A, Stone J, Lynch L, Lapinski R, Berkowitz G, Berkowitz RL. Pregnancy outcome at age 40 and older. Obstet Gynecol 1996;87: 917-22.
Saftlas AF, Olson DR, Franks Al, Atrash HK, Pokras R. Epidemiology of preeclampsia and eclampsia in the United states, 1979-1986. Am J Obstet Gynecol 1990;163: 460-5.
Coonrod DV, Hickok DE, Zhu K, Easterling TR, Daling JR. Risk factors for preeclampsia in twin pregnancies: a population-based cohort study. Obstet Gynecol 1995;85: 645-50.
Lawoyin TO, Ani F. Epidemiologic aspects of pre-eclampsia in Saudi Arabia. East Afr Med J 1996;73: 404-6.
Lee CJ, Hsieh TT, Chiu TH, Chen KC, Lo LM, Hung TH. Risk factors for pre-eclampsia in an Asian population. Int J Gynecol Obstet 2000;70: 327-33.
Khan KS, Daya S. Plasma glucose and pre-eclampsia. Int J Gynecol Obstet 1996;53: 111-6.
Hartikainen A, Aliharmi RH, Rantakallio PT. A cohort study of epidemiological associations and outcomes of pregnancies with hypertensive disorders. Hypertens Pregnancy 1998;17: 31-41.
Eskenazi B, Fenster L, Sidney SA. Multivariate analysis of risk factors for preeclampsia. JAMA 1991;266: 237-41.
Stone JL, Lockwood CJ, Berkowitz GS, Alvarez M, Lapinski R, Berkowitz RL. Risk factors for severe preeclampsia. Obstet Gynecol 1994;83: 357-61.
Chen CL, Cheng Y, Wang PH, Juang CM, Chiu LM, Yang MJ, et al. Review of pre-eclampsia in Taiwan: a multi-institutional study. Zhonghua Yi Xue Za Zhi (Taipei) 2000;63: 869-75.
Odegard RA, Vatten LJ, Nilsen ST, Salvesen KA, Austgulen R. Risk factors and clinical manifestations of pre-eclampsia. Br J Obstet Gynaecol 2000;107: 1410-6.
Stamilio DM, Sehdev HM, Morgan MA, Propert K, Macones GA. Can antenatal clinical and biochemical markers predict the development of severe preeclampsia? Am J Obstet Gynecol 2000;182: 589-94.
Campbell DM, MacGillivray I, Carr-Hill R. Pre-eclampsia in second pregnancy. Br J Obstet Gynaecol 1985;92: 131-40.
Sibai BM, El Nazer A, Gonzalez-Ruiz A. Severe preeclampsia-eclampsia in young primigravid women: subsequent pregnancy outcome and remote prognosis. Am J Obstet Gynecol 1986;155: 1011-6.
Makkonen N, Heinonen S, Kirkinen P. Obstetric prognosis in second pregnancy after preeclampsia in first pregnancy. Hypertens Pregnancy 2000;19: 173-81.
Dukler D, Porath A, Bashiri A, Erez O, Mazor M. Remote prognosis of primiparous women with preeclampsia. Eur J Obstet Gynecol Reprod Biol 2001;96: 69-74.
Moore MP, Redman CW. Case-control study of severe pre-eclampsia of early onset. BMJ 1983;287: 580-3.
Davies AM, Czaczkes JW, Sadovsky E, Prywes R, Weiskopf P, SterkVV. Toxemia of pregnancy in Jerusalem I. Epidemiological studies of a total community. Isr J Med Sci 1970;6: 253-66.
Banias BB, Devoe LD, Nolan TE. Severe preeclampsia in preterm pregnancy between 26 and 32 weeks' gestation. Am J Perinatol 1992;9: 357-60.
Arngrimsson R, Bjornsson S, Geirsson RT, Bjornsson H, Walker JJ, Snaedal G. Genetic and familial predisposition to eclampsia and pre-eclampsia in a defined population. Br J Obstet Gynaecol 1990;97: 762-9.
Cincotta RB, Brennecke SP. Family history of pre-eclampsia as a predictor for pre-eclampsia in primigravidas. Int J Gynaecol Obstet 1998;60: 23-7.
Sutherland A, Cooper DW, Howie PW, Liston WA, MacGillivray I. The incidence of severe pre-eclampsia amongst mothers and mothers-in-law of pre-eclamptics and controls. Br J Obstet Gynaecol 1981;88: 785-91.
Santema JG, Koppelaar I, Wallenburg HC. Hypertensive disorders in twin pregnancy. Eur J Obstet Gynecol Reprod Biol 1995;58: 9-13.
Ros HS, Cnattingius S, Lipworth L. Comparison of risk factors for preeclampsia and gestational hypertension in a population-based cohort study. Am J Epidemiol 1998;147;11(suppl): 1062-70.
Maxwell CV, Lieberman E, Norton M, Cohen A, Seely EW, Lee-Parritz A. Relationship of twin zygosity and risk of preeclampsia. Am J Obstet Gynecol 2001;185: 819-21.
Savvidou MD, Karanastasi E, Skentou C, Geerts L, Nicolaides KH. Twin chorionicity and pre-eclampsia. Ultrasound Obstet Gynecol 2001;18: 228-31.
Skupski DW, Nelson S, Kowalik A, Polaneczky M, Smith-Levitin M, Hutson JM, Rosenwaks Z. Multiple gestations from in vitro-fertilization: Successful implantation alone is not associated with subsequent pre-eclampsia. Am J Obstet Gynecol 1996;175: 1029-32.
Garner PR, D'Alton ME, Dudley DK, Huard P, Hardie M. Preeclampsia in diabetic pregnancies. Am J Obstet Gynecol 1990;163: 505-8.
McCowan LM, Buist RG, North RA, Gamble G. Perinatal morbidity in chronic hypertension. Br J Obstet Gynaecol 1996;103: 123-9.
Martinell J, Jodal U, Lidin-Janson G. Pregnancies in women with and without renal scarring after urinary infections in childhood. BMJ 1990;300: 840-4.
Pattison NS, Chamley LW, McKay EJ, Liggins GC, Butler WS. Antiphospholipid antibodies in pregnancy: prevalence and clinical associations. Br J Obstet Gynaecol 1993;100: 909-13.
Yasuda M, Takakuwa K, Tokunaga A, Tanaka K. Prospective studies of the association between anticardiolipin antibody and outcome of pregnancy. Obstet Gynecol 1995;86: 555-9.
Branch DW, Andres R, Digre KB, Rote NS, Scott JR. The association of antiphospholipid antibodies with severe preeclampsia. Obstet Gynecol 1989;73: 541-5.
Sletnes KE, Wisloff F, Moe N, Dale PO. Antiphospholipid antibodies in pre-eclamptic women: relation to growth retardation and neonatal outcome. Acta Obstet Gynecol Scand 1992;71: 112-7.
Dreyfus M, Hedelin G, Kutnahorsky R, Lehmann M, Vivelle B, Langer B, et al. Antiphospholipid antibodies and preeclampsia: a case-control study. Obstet Gynecol 2001;97: 29-34.
Skjaerven R, Wilcox AJ, Lie RT. The interval between pregnancies and the risk of preeclampsia. N Engl J Med 2002;346: 33-8.
Conde-Agudelo A, Belizan JM. Maternal morbidity and mortality associated with interpregnancy interval: cross sectional study. BMJ 2000;321: 1255-9.
Basso O, Christensen K, Olsen J. Higher risk of pre-eclampsia after change of partner. An effect of longer interpregnancy intervals? Epidemiology 2001;12: 624-9.
Bianco AT, Smilen SW, Davis Y, Lopez S, Lapinski R, Lockwood CJ. Pregnancy outcome and weight gain recommendations for the morbidly obese woman. Obstet Gynecol 1998;91: 97-102.
Fields SJ, Vainder M, Livshits G, Merlob P, Sirotta L. Obesity and the risk of toxaemia of pregnancy. Ann Hum Biol 1996;23: 353-62.
Thadhani R, Stampfer MJ, Hynter DJ, Manson JE, Solomon CG, Curhan GC. High body mass index and hypercholesterolaemia: risk of hypertensive disorders of pregnancy. Obstet Gynecol 1999;94: 543-50.
Sibai BM, Ewell M, Levine RJ, Klebanoff MA, Esterlitz J, Catalano PM, et al. Risk factors associated with preeclampsia in healthy nulliparous women. The Calcium for Preeclampsia Prevention (CPEP) Study Group. Am J Obstet Gynecol 1997;177: 1003-10.
Bowers D, Cohen WR. Obesity and related pregnancy complications in an inner-city clinic. J Perinatol 1999;19: 216-9.
Van Hoorn J, Dekker G, Jeffries B. Gestational diabetes versus obesity as risk factors for pregnancy-induced hypertensive disorders and fetal macrosomia. Aust N Z J Obstet Gynaecol 2002;42: 29-34.
Sebire NJ, Harris J, Regan L, Robinson S. Is maternal underweight really a risk factor for adverse pregnancy outcome? A population-based study in London. Br J Obstet Gynaecol 2001;108: 61-6.
Reiss RE, O'Shaughnessy RW, Quilligan TJ, Zuspan FP. Retrospective comparison of blood pressure course during preeclamptic and matched control pregnancies. Am J Obstet Gynecol 1987;156: 894-8.
Sibai BM, Gordon T, Thom E, Caritis SN, Klebanoff M, McNellis D, et al. Risk factors for preeclampsia in healthy nulliparous women: a prospective multicenter study. Am J Obstet Gynecol 1995;172: 642-8.
Sattar N, Clark P, Holmes A, Lean MEJ, Walker I, Greer IA. Antenatal waist circumference and hypertension risk. Obstet Gynecol 2001;97: 268-71.
Bradford JA, Giles WB. Teenage pregnancy in western Sydney. Aust N Z J Obstet Gynaecol 1989;29: 1-4.
Brown HL, Fan YD, Gonsoulin WJ. Obstetric complications in young teenagers. S Med J 1964;84: 46-8.
Konje JC, Palmer A, Watson A, Hay DM, Imrie A, Ewings P. Early teenage pregnancies in Hull. Br J Obstet Gynaecol 1992;99: 969-73.
Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet 1991;337: 867-72.
Chalmers TC, Levin H, Sacks HS. Meta-analysis of clinical trials as a scientific discipline. I: control of bias and comparison with large co-operative trials. Stat Med 1987;6: 315-25.
Mattar F, Sibai BM. Eclampsia. VIII. Risk factors for maternal morbidity. Am J Obstet Gynecol 2000;182: 307-12.
Milne F, Redman C, Walker J, Baker P, Bradley J, Cooper C, et al. The pre-eclampsia community guideline (PRECOG): how to screen for and detect onset of pre-eclampsia in the community. BMJ 2005 (in press).(Kirsten Duckitt)