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Risk factors for pre-eclampsia in an Asian population
International Journal of Gynecology & Obstetrics 70 Ž2000. 327᎐333
Article
Risk factors for pre-eclampsia in an Asian population C.-J. Lee, T.-T. Hsieh, T.-H. Chiu, K.-C. Chen, L.-M. Lo, T.-H. HungU,1 Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan Received 13 November 1999; received in revised form 25 February 2000; accepted 10 March 2000
Abstract Objecti¨ e: To identify the risk factors for pre-eclampsia in an Asian population. Method: We conducted a retrospective cohort study involving 29 375 Taiwanese women who delivered between July 1990 and September 1998, excluding pregnancies complicated by chronic hypertension or fetal malformations. Result: Four hundred and fifteen women had pre-eclampsia Ž1.4%.. Women who had a history of pre-eclampsia ŽOR 6.3, 95% CI 4.4, 9.2., multiple gestation ŽOR 3.6, 95% CI 2.4, 5.5., a prepregnancy BMI ) 24.2 kgrm2 ŽOR 2.4, 95% CI 1.8, 3.1., were ) 34 years of age ŽOR 1.8, 95% CI 1.4, 2.4., nulliparous ŽOR 1.3, 95% CI 1.2, 1.5., had urinary tract infection ŽOR 4.8, 95% CI 1.5, 15.8., or worked during pregnancy ŽOR 1.9, 95% CI 1.4, 2.4. were at increased risk of pre-eclampsia. Conclusion: Some of the risk factors for pre-eclampsia among Asian women are the same as those of other ethnic groups, whereas some of the risk factors are different. 䊚 2000 International Federation of Gynecology and Obstetrics. Keywords: Risk factor; Pre-eclampsia
1. Introduction The etiology of pre-eclampsia is unknown w1x. Because of the lack of proven prevention for pre-eclampsia w2x, prediction of risk or identifica-
U
Corresponding author. Tel.: q886-2-2713-5211; fax: q886-2-2719-7368. E-mail address: [email protected] ŽT.-H. Hung.. 1 Present address: Department of Anatomy, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK. Fax: q44-1223-333786.
tion of sub-clinical disease is desirable to identify patients for more intensive observation. Numerous risk factors for pre-eclampsia have been suggested w3᎐15x, but only some have actually been established in multivariate models that permit simultaneous control for possible confounders. In addition, many past findings lead to conflicting results w3,13,14x as some previous multivariate analyses had limited sample size w7,8,12᎐14x or only retrospectively evaluated birth certificates, which were often incomplete and subject to misclassification w5,7,12,15x.
0020-7292r00r$20.00 䊚 2000 International Federation of Gynecology and Obstetrics. PII: S 0 0 2 0 - 7 2 9 2 Ž 0 0 . 0 0 2 4 0 - X
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C.-J. Lee et al. r International Journal of Gynecology & Obstetrics 70 (2000) 327᎐333
Significant differences had been found in the prevalence of these risk factors in Asians as compared to other ethnic groups, involving blood pressure, obesity, and maternal age adjusted for parity w9x. Furthermore, there has not been any previous large-scale report concerning the risk factors for pre-eclampsia in an Asian population. Therefore, the objective of the present study is to identify clinical risk factors associated with preeclampsia, in a large cohort of Taiwanese.
2. Materials and method Information for this study was abstracted from the Chang Gung Memorial Hospital’s computerized obstetric database. We included all deliveries between July 1990 and September 1998 Ž n s 37 287. for analysis. Pregnancies complicated with chronic hypertension Ža prepregnancy diagnosis of hypertension or, if previously unknown, a diagnosis of hypertension before the 20th week of gestation, n s 43. and fetal malformations Žstructural or chromosomal, n s 499. were excluded. If a woman was involved more than once during the study period, a computer-generated random number was assigned to each pregnancy, and the pregnancy with the smallest number was selected for analysis. A total of 29 735 pregnancies constitute the population of this study. Every woman received a detailed inquiry about her pregnancy, medical history, and exposure to potential risk factors during her first antenatal visit. Pregnancy outcome information was taken from labor and delivery records and reviewed weekly, with a postpartum interview, if necessary, to collect supplemental information. In this study, pre-eclampsia was defined, according to the guidelines of the International Society for the Study of Hypertension in Pregnancy w16x, as gestational hypertension with proteinuria in previously normotensive women. Gestational hypertension was defined as two recordings of diastolic blood pressure of 90 mmHg or higher at least 4 h apart after 20 weeks’ gestation. Proteinuria was defined as excretion of ) 300 mg of urinary protein in 24 h or two readings of ) 2 q protein on dipstick analysis of midstream
or catheter urine specimens, if 24-h collection was not available. The following maternal reproductive risk factors were evaluated as potential confounding factors: age at delivery Žcategorized into three groups: less than 20 years, 20᎐34 years, and more than 34 years.; gravidity; parity; prepregnancy weight; body mass index wBMI, calculated as weight Žkg.rheight Žm. 2 and categorized as underweight ŽBMI - 19.8., normal weight ŽBMI 19.8᎐24.2., and overweight or obese ŽBMI ) 24.2. w17xx; years of education; marital status; having worked during pregnancy; multiple gestation; conception method Žnatural or assisted by reproductive techniques .; fetal gender; obstetric history Žprevious pre-eclampsia, fetal death and abortion including induced or spontaneous.; diabetes mellitus Žovert or gestational.; urinary tract infection Žincluding asymptomatic bacteriuria, cystitis and pyelonephritis. during pregnancy; and uterine fibroids. For statistical analysis, we used SPSS for Windows, Release 7.0 ŽStatistical Package for Social Sciences Inc., Chicago, IL, USA.. Student’s t-test was used for continuous variables. 2 and Fisher’s exact tests were used to analyze categorical variables. Multivariate logistic regression was used to evaluate the association between pre-eclampsia and the various risk factors, while controlling for potential confounders. Adjusted odds ratios ŽORs. were calculated to approximate the relative risk from the regression coefficients, and the associated standard errors were used to determine 95% confidence intervals ŽCIs..
3. Results Four hundred and fifteen of 29 735 women had pre-eclampsia Ž1.4%.. Tables 1 and 2 demonstrate selected demographic characteristics and perinatal outcomes of the study population, respectively. The mean maternal age at delivery and prepregnancy weight were significantly higher in women with pre-eclampsia than in controls. Furthermore, the frequencies of prepregnancy BMI ) 24.2 kgrm2 , preterm delivery, birth weight - 1500 g, Apgar scores - 7 at 1 and 5 min, cesarean deliv-
C.-J. Lee et al. r International Journal of Gynecology & Obstetrics 70 (2000) 327᎐333
329
Table 1 Demographic characteristics of study populationa Variable
Pre-eclampsia Ž n s 415.
Control cohort Ž n s 29 320.
Pb
Age Žyears. Gravidity Parity Prepregnancy weight Žkg. Prepregnancy body mass index Žkgrm2 . - 19.8 19.8᎐24.2 Žreference . ) 24.2 Education Žyears. -7 7᎐12 Žreference . ) 12
30.8" 4.7 2.4" 1.5 1.6" 0.9 52.5" 17.1
29.9" 4.1 2.3" 1.3 1.7" 0.8 49.5" 12.7
- 0.01 0.33 0.21 - 0.01
80 Ž19.3%. 261 Ž62.9%. 74 Ž17.8%.
9799 Ž33.4%. 17 489 Ž59.6%. 2032 Ž6.9%.
- 0.01 ) 0.999 - 0.01
40 Ž9.6%. 359 Ž86.5%. 16 Ž3.9%.
2214 Ž7.6%. 25 917 Ž88.4%. 1189 Ž4.1%.
0.11 ) 0.999 0.91
a b
Data are presented as mean " standard deviation or n Ž%.. P-value based on 2-test for categorical variables and Student’s t-test for continuous ones.
ery, neonatal intensive care unit transfer, neonatal death and abruptio placenta were also statistically higher in women with pre-eclampsia. Table 3 compares the frequency of different potential determinants in pre-eclampsia and the control cohort. Women with pre-eclampsia had a higher frequency of age ) 34 years, nulliparity, a prepregnancy BMI ) 24.2 kgrm2 , having worked during pregnancy, multiple gestation, undergoing assisted reproductive techniques, having a history of pre-eclampsia, overt or gestational diabetes, urinary tract infection during pregnancy and uterine fibroids. On the other hand, a prepregnancy BMI - 19.8 kgrm2 was found to be inversely related to the occurrence of pre-eclampsia. The result of multivariate logistic regression with adjustment for the confounding effect of the above determinants significant by univariate analysis is shown in Table 4. Women who had a history of pre-eclampsia ŽOR 6.3, 95% CI 4.4, 9.2., multiple gestation ŽOR 3.6, 95% CI 2.4, 5.5., a prepregnancy BMI ) 24.2 kgrm2 ŽOR 2.4, 95% CI 1.8, 3.1., were ) 34 years of age ŽOR 1.8, 95% CI 1.4, 2.4., nulliparous ŽOR 1.3, 95% CI 1.2,1.5., had urinary tract infection ŽOR 4.8, 95% CI 1.5, 15.8., or having worked during pregnancy ŽOR 1.9, 95% CI 1.4, 2.4. had an increased risk for pre-eclampsia. On the other hand, a low prepreg-
nancy BMI Ž- 19.8 kgrm2 . was found to be protective against the development of pre-eclampsia ŽOR 0.6, 95% CI 0.4, 0.7..
4. Discussion To our knowledge, this is the largest retrospective cohort study of the risk factors for preeclampsia in an Asian population. The strengths of this study were the use of patient interview and medical record data and the ability to control for possible confounding factors, which enabled an objective investigation into the influence of different risk factors for pre-eclampsia. The prevalence of pre-eclampsia in our institution is 1.4%, which is lower than that of previous reports from mostly non-Asian women w3᎐5,11,12,18x. This finding indicates that preeclampsia might be a relatively uncommon disease in Taiwan, because of our adaptation to universal diagnostic criteria, a weekly chart review, and the case concentration effort of our hospital, which is a referral medical center in Northern Taiwan. Therefore, the frequency of pre-eclampsia in our general population would be even lower. The reason for this disparity remains unknown; however, we believe that a difference
330
C.-J. Lee et al. r International Journal of Gynecology & Obstetrics 70 (2000) 327᎐333
Table 2 Perinatal outcome of pre-eclampsiaa Variable
Pre-eclampsia Control cohort Pb Ž n s 415. Ž n s 29 320.
Preterm delivery Yes 172 Ž41.4%. No 243 Ž58.6%. Birth weight less than 1500 g Yes 50 Ž12.0%. No 365 Ž88.0%. 1-min Apgar score - 7 Yes 78 Ž18.8%. No 337 Ž81.2%. 5-min Apgar score - 7 Yes 29 Ž7.0%. No 386 Ž93.0%. Cesarean delivery Yes 315 Ž75.9%. No 100 Ž24.1%. NICU transfer Yes 110 Ž26.5%. No 305 Ž73.5%. Fetal death Yes 5 Ž1.2%. No 410 Ž98.8%. Neonatal death Yes 12 Ž2.9%. No 403 Ž97.1%. Postpartum hemorrhage Yes 30 Ž7.2%. No 385 Ž92.8%. Abruptio placenta Yes 21 Ž5.1%. No 394 Ž94.9%. Placenta previa Yes 9 Ž2.2%. No 406 Ž97.8%.
2007 Ž6.8%. - 0.01 27 313 Ž93.2%.
345 Ž1.2%. - 0.01 28 975 Ž98.8%. 833 Ž2.8%. - 0.01 28 487 Ž97.2%. 405 Ž1.4%. - 0.01 28 915 Ž98.6%. 11 167 Ž38.1%. - 0.01 18 153 Ž61.9%. 1308 Ž4.5%. - 0.01 28 012 Ž95.5%. 170 Ž0.6%. 29 150 Ž99.4%.
0.10
94 Ž0.3%. - 0.01 29 226 Ž99.7%. 2007 Ž6.8%. 27 313 Ž93.2%.
0.77
271 Ž0.9%. - 0.01 29 049 Ž99.1%. 321 Ž1.1%. 28 999 Ž98.9%.
0.05
a Abbre¨ iation: NICUs neonatal intensive care unit. Data are presented as n Ž%.. b P-values based on 2-tests.
in the prevalence of variable risk factors for preeclampsia Ži.e. less prepregnancy obese, and more underweight women. between different ethnicities may partially contribute to this discrepancy, in addition to other environmental or genetic effects. Consistent with previous reports w4᎐6,8,14x, we found that obese women, defined as having a prepregnancy BMI ) 24.2 kgrm2 in this study, carried an increased risk of developing pre-
eclampsia. Furthermore, a prepregnancy BMI 19.8 kgrm2 was found to be protective against the disease. Eskenazi et al. w14x had demonstrated a similar result, but the protective effect of prepregnancy underweight did not reach statistical significance, possibly due to limited samples in their study. It has been observed that obese women were more likely to have increased levels of serum triglycerides, very low-density lipoproteins, and formation of small, dense low-density lipoprotein particles w19x. A similar lipid profile has also been found in women with pre-eclampsia w20x. Such lipid alterations have been suggested to promote oxidative stress, caused by either ischemia-reperfusion mechanism or activated neutrophils, and lead to endothelial cell dysfunction w1,21x. Unlike previous reports w14,15x, we found that women) 34 years of age were at increased risk of pre-eclampsia, even when excluding those with chronic hypertension. Such an association may be related to the progressive vascular endothelial damage that occurs with aging. Naeye w22x reported that, in a series of 62 autopsies, the incidence of sclerotic lesions in myometrial arteries increased with aging, from 11% at age 17᎐19 years to 61% at age 30᎐39 years, and 83% after age 39. Obstruction of the maternal spiral arteriolar lumina by atherosis has been frequently observed in pregnancies complicated by preeclampsia w23x. Therefore, we believe women at an advanced age should be followed carefully for the possible development of pre-eclampsia. Our observation confirmed most previous studies that nulliparity, multiple gestations and a history of pre-eclampsia were significant risk factors for pre-eclampsia, consistent with the hypothesis that immune maladaptation might play a role in triggering the development of pre-eclampsia w1x. Nevertheless, we did not demonstrate that having a previous history of abortion protected against pre-eclampsia. A minor limitation of the present study is the inability to differentiate between spontaneous and induced abortion because of the lack of information on this variable. Some workers w14x suggested previously that a history of spontaneous abortion, which usually occurs later in gestation than therapeutic abortions, provided
C.-J. Lee et al. r International Journal of Gynecology & Obstetrics 70 (2000) 327᎐333
protection against pre-eclampsia. In pre-eclamptic pregnancies, there is failure of the second wave of trophoblastic invasion in the second trimester ex-
331
tending into the inner one-third of the myometrium. We hypothesized that if an abortion occurs beyond the critical point of triggering the
Table 3 Potential determinants of pre-eclampsiaa Potential determinant
Age Žyears. - 20 20᎐34 Žreference . ) 34 Nulliparous Yes No Prepregnancy body mass index Žkgrm2 . - 19.8 19.8᎐24.2 Žreference . ) 24.2 Education Žyears. -7 7᎐12 Žreference . ) 12 Unmarried Yes No Worked during pregnancy Yes No Multiple gestation Yes No Conception assisted by reproductive techniques Yes No Fetal male gender Yes No History of abortion Yes No History of fetal death Yes No History of pre-eclampsiac Yes No Overt diabetes Yes No Gestational diabetes Yes No
Pre-eclampsia Ž n s 415.
Control cohort Ž n s 29 320.
Pb
2 Ž0.5%. 321 Ž77.3%. 92 Ž22.2%.
201 Ž0.7%. 25 367 Ž86.5%. 3752 Ž12.8%.
0.73 ) 0.999 - 0.01
245 Ž59.0%. 170 Ž41.0%.
14 576 Ž49.7%. 14 744 Ž50.3%.
- 0.01
80 Ž19.3%. 261 Ž62.9%. 74 Ž17.8%.
9799 Ž33.4%. 17 489 Ž59.6%. 2032 Ž6.9%.
- 0.01 ) 0.999 - 0.01
40 Ž9.6%. 359 Ž86.5%. 16 Ž3.9%.
2214 Ž7.6%. 25 917 Ž88.4%. 1189 Ž4.1%.
0.11 ) 0.999 0.91
2 Ž0.5%. 413 Ž99.5%.
109 Ž0.4%. 29 211 Ž99.6%.
0.67
353 Ž85.1%. 62 Ž14.9%.
21 043 Ž71.8%. 8277 Ž28.2%.
- 0.01
34 Ž8.2%. 381 Ž91.8%.
514 Ž1.8%. 28 806 Ž98.2%.
- 0.01
14 Ž3.4%. 401 Ž96.6%.
357 Ž1.2%. 28 963 Ž98.8%.
- 0.01
204 Ž49.2%. 211 Ž50.8%.
15 527 Ž53.0%. 13 793 Ž47.0%.
0.13
188 Ž45.3%. 227 Ž54.7%.
12 684 Ž43.3%. 16 636 Ž56.7%.
0.43
10 Ž2.4%. 405 Ž97.6%.
302 Ž1.0%. 29 018 Ž99.0%.
- 0.05
19 Ž11.2%. 151 Ž88.8%.
242 Ž1.6%. 14 502 Ž98.4%.
- 0.01
3 Ž0.7%. 412 Ž99.3%.
55 Ž0.2%. 29 265 Ž99.8%.
- 0.05
33 Ž8.0%. 382 Ž92.0%.
1376 Ž4.7%. 27 944 Ž95.3%.
- 0.01
C.-J. Lee et al. r International Journal of Gynecology & Obstetrics 70 (2000) 327᎐333
332 Table 3 Ž Continued. Potential determinant
Urinary tract infection during pregnancy Yes No Uterine fibroids Yes No
Pre-eclampsia Ž n s 415.
Control cohort Ž n s 29 320.
Pb
3 Ž0.7%. 412 Ž99.3%.
50 Ž0.2%. 29 270 Ž99.8%.
- 0.05
8 Ž1.9%. 407 Ž98.1%.
195 Ž0.7%. 29 125 Ž99.3%.
- 0.01
a
Data are presented as n Ž%.. P-values based on 2-tests for categorical variables and Student’s t-test for continuous ones. c Only includes those women who had given birth previously. b
immune mechanisms involved in the etiology of pre-eclampsia, it can provide some protection against the disease. Therefore, a mixture of induced and spontaneous abortions will inevitably mask the protective effect of an abortion at late gestation. Further investigations regarding the association of abortions at different gestation and pre-eclampsia are needed in order to test the above hypotheses. Although we have found that urinary tract infection and working during pregnancy were significantly associated with pre-eclampsia, another limitation of this study is that diagnosis of urinary tract infection was not exclusively confirmed by urine culture, and information about the length of employment during pregnancy was not consistently provided on the medical chart and, thereTable 4 Results of multivariate logistic regression a
References
Potential determinant
Adjusted OR
95% CI
History of pre-eclampsia Multiple gestation Prepregnancy body mass index ) 24.2 kgrm2 Age ) 34 years Nulliparity Urinary tract infection during pregnancy Worked during pregnancy Prepregnancy body mass index - 19.8 kgrm2
6.3 3.6 2.4
4.4, 9.2 2.4, 5.5 1.8, 3.1
1.8 1.3 4.8
1.4, 2.4 1.2, 1.5 1.5, 15.8
1.9 0.6
1.4, 2.4 0.4, 0.7
a
fore, was not abstracted. Biologic mechanisms behind the association between these two risk factors and pre-eclampsia still remain unclear, although a correlate of prior infectious renal damage w6x or underlying renal disease w11x, stress and decreased leisure-time activity w10,14x have been proposed to predispose the gravid women to pre-eclampsia. However, further studies, especially those using histopathologic evidence, are needed to clarify such a relationship. This study provided useful clinical information for practitioners counseling Asian women regarding pre-eclampsia. In addition, the association documented here provides compelling support for the screening of at-risk women. These subsets of women are ideal for the further study of preeclampsia and its treatment or possible prevention.
Abbre¨ iations: OR, odds ratio; and CI, confidence interval.
w1x Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia: current concepts. Am J Obstet Gynecol 1998;179:1359᎐1375. w2x Sibai BM. Prevention of preeclampsia: a big disappointment. Am J Obstet Gynecol 1998;179:1275᎐1278. w3x 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. The National Institute of Child Health and Human Development Network of Maternal᎐Fetal Medicine Units. Am J Obstet Gynecol 1995;172:642᎐648. w4x Sibai BM, Ewell M, Levine RJ, Klebanoff MA, Esterlitz J, Catalano PM et al. Risk factors associated with
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preeclampsia in healthy nulliparous women. The Calcium for Preeclampsia Prevention ŽCPEP. Study Group. Am J Obstet Gynecol 1997;177:1003᎐1010. 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; 147:1062᎐1070. Mittendorf R, Lain KY, Williams MA, Walker CK. Preeclampsia. A nested, case-control study of risk factors and their interactions. J Reprod Med 1996; 41:491᎐496. Misra DP, Kiely JL. The association between nulliparity and gestational hypertension. J Clin Epidemiol 1997; 50:851᎐855. Mahomed K, Williams MA, Woelk GB, Jenkins-Woelk L, Mudzamiri S, Longstaff L et al. Risk factors for pre-eclampsia among Zimbabwean women: maternal arm circumference and other anthropometric measures of obesity. Paediatr Perinat Epidemiol 1998;12:253᎐262. Knuist M, Bonsel GJ, Zondervan HA, Treffers PE. Risk factors for preeclampsia in nulliparous women in distinct ethnic groups: a prospective cohort study. Obstet Gynecol 1998;92:174᎐178. Klebanoff MA, Shiono PH, Rhoads GG. Outcomes of pregnancy in a national sample of resident physicians. N Engl J Med 1990;323:1040᎐1045. Hsu CD, Witter FR. Urogenital infection in preeclampsia. Int J Gynaecol Obstet 1995;49:271᎐275. Gunnlaugsson SR, Geirsson RT, Snaedal G, Hallgrimsson JT. Incidence and relation to parity of pregnancy-induced hypertension in Iceland. Acta Obstet Gynecol Scand 1989;68:599᎐601. Fields SJ, Vainder M, Livshits G, Merlob P, Sirotta L. Obesity and the risk of toxaemia of pregnancy. Ann Hum Biol 1996;23:353᎐362.
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w14x Eskenazi B, Fenster L, Sidney S. A multivariate analysis of risk factors for preeclampsia. J Am Med Assoc 1991;266:237᎐241. w15x 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᎐650. w16x Davey DA, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy. Am J Obstet Gynecol 1988;158:892᎐898. w17x Hsieh TT, Chang TC, Hung TH, Su CH, Hsieh CC, Hsu JJ. Maternal weight gain during pregnancy and risks of small for gestational age and large for gestational age newborns. J Matern Fetal Invest 1997;7:60᎐64. w18x 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᎐465. w19x James RW, Brulhart-Meynet MC, Lehmann T, Golay A. Lipoprotein distribution and composition in obesity: their association with central adiposity. Int J Obes Relat Metab Disord 1997;21:1115᎐1120. w20x Sattar N, Bendomir A, Berry C, Shepherd J, Greer IA, Packard CJ. Lipoprotein subfraction concentrations in preeclampsia: pathogenic parallels to atherosclerosis. Obstet Gynecol 1997;89:403᎐408. w21x Hubel CA. Oxidative stress in the pathogenesis of preeclampsia. Proc Soc Exp Biol Med 1999;222:222᎐235. w22x Naeye RL. Maternal age, obstetric complications, and the outcome of pregnancy. Obstet Gynecol 1983;61: 210᎐216. w23x Rogers BB, Bloom SL, Leveno KJ. Atherosis revisited: current concepts on the pathophysiology of implantation site disorders. Obstet Gynecol Surv 1999;54:189᎐195.
Article
Risk factors for pre-eclampsia in an Asian population C.-J. Lee, T.-T. Hsieh, T.-H. Chiu, K.-C. Chen, L.-M. Lo, T.-H. HungU,1 Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan Received 13 November 1999; received in revised form 25 February 2000; accepted 10 March 2000
Abstract Objecti¨ e: To identify the risk factors for pre-eclampsia in an Asian population. Method: We conducted a retrospective cohort study involving 29 375 Taiwanese women who delivered between July 1990 and September 1998, excluding pregnancies complicated by chronic hypertension or fetal malformations. Result: Four hundred and fifteen women had pre-eclampsia Ž1.4%.. Women who had a history of pre-eclampsia ŽOR 6.3, 95% CI 4.4, 9.2., multiple gestation ŽOR 3.6, 95% CI 2.4, 5.5., a prepregnancy BMI ) 24.2 kgrm2 ŽOR 2.4, 95% CI 1.8, 3.1., were ) 34 years of age ŽOR 1.8, 95% CI 1.4, 2.4., nulliparous ŽOR 1.3, 95% CI 1.2, 1.5., had urinary tract infection ŽOR 4.8, 95% CI 1.5, 15.8., or worked during pregnancy ŽOR 1.9, 95% CI 1.4, 2.4. were at increased risk of pre-eclampsia. Conclusion: Some of the risk factors for pre-eclampsia among Asian women are the same as those of other ethnic groups, whereas some of the risk factors are different. 䊚 2000 International Federation of Gynecology and Obstetrics. Keywords: Risk factor; Pre-eclampsia
1. Introduction The etiology of pre-eclampsia is unknown w1x. Because of the lack of proven prevention for pre-eclampsia w2x, prediction of risk or identifica-
U
Corresponding author. Tel.: q886-2-2713-5211; fax: q886-2-2719-7368. E-mail address: [email protected] ŽT.-H. Hung.. 1 Present address: Department of Anatomy, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK. Fax: q44-1223-333786.
tion of sub-clinical disease is desirable to identify patients for more intensive observation. Numerous risk factors for pre-eclampsia have been suggested w3᎐15x, but only some have actually been established in multivariate models that permit simultaneous control for possible confounders. In addition, many past findings lead to conflicting results w3,13,14x as some previous multivariate analyses had limited sample size w7,8,12᎐14x or only retrospectively evaluated birth certificates, which were often incomplete and subject to misclassification w5,7,12,15x.
0020-7292r00r$20.00 䊚 2000 International Federation of Gynecology and Obstetrics. PII: S 0 0 2 0 - 7 2 9 2 Ž 0 0 . 0 0 2 4 0 - X
328
C.-J. Lee et al. r International Journal of Gynecology & Obstetrics 70 (2000) 327᎐333
Significant differences had been found in the prevalence of these risk factors in Asians as compared to other ethnic groups, involving blood pressure, obesity, and maternal age adjusted for parity w9x. Furthermore, there has not been any previous large-scale report concerning the risk factors for pre-eclampsia in an Asian population. Therefore, the objective of the present study is to identify clinical risk factors associated with preeclampsia, in a large cohort of Taiwanese.
2. Materials and method Information for this study was abstracted from the Chang Gung Memorial Hospital’s computerized obstetric database. We included all deliveries between July 1990 and September 1998 Ž n s 37 287. for analysis. Pregnancies complicated with chronic hypertension Ža prepregnancy diagnosis of hypertension or, if previously unknown, a diagnosis of hypertension before the 20th week of gestation, n s 43. and fetal malformations Žstructural or chromosomal, n s 499. were excluded. If a woman was involved more than once during the study period, a computer-generated random number was assigned to each pregnancy, and the pregnancy with the smallest number was selected for analysis. A total of 29 735 pregnancies constitute the population of this study. Every woman received a detailed inquiry about her pregnancy, medical history, and exposure to potential risk factors during her first antenatal visit. Pregnancy outcome information was taken from labor and delivery records and reviewed weekly, with a postpartum interview, if necessary, to collect supplemental information. In this study, pre-eclampsia was defined, according to the guidelines of the International Society for the Study of Hypertension in Pregnancy w16x, as gestational hypertension with proteinuria in previously normotensive women. Gestational hypertension was defined as two recordings of diastolic blood pressure of 90 mmHg or higher at least 4 h apart after 20 weeks’ gestation. Proteinuria was defined as excretion of ) 300 mg of urinary protein in 24 h or two readings of ) 2 q protein on dipstick analysis of midstream
or catheter urine specimens, if 24-h collection was not available. The following maternal reproductive risk factors were evaluated as potential confounding factors: age at delivery Žcategorized into three groups: less than 20 years, 20᎐34 years, and more than 34 years.; gravidity; parity; prepregnancy weight; body mass index wBMI, calculated as weight Žkg.rheight Žm. 2 and categorized as underweight ŽBMI - 19.8., normal weight ŽBMI 19.8᎐24.2., and overweight or obese ŽBMI ) 24.2. w17xx; years of education; marital status; having worked during pregnancy; multiple gestation; conception method Žnatural or assisted by reproductive techniques .; fetal gender; obstetric history Žprevious pre-eclampsia, fetal death and abortion including induced or spontaneous.; diabetes mellitus Žovert or gestational.; urinary tract infection Žincluding asymptomatic bacteriuria, cystitis and pyelonephritis. during pregnancy; and uterine fibroids. For statistical analysis, we used SPSS for Windows, Release 7.0 ŽStatistical Package for Social Sciences Inc., Chicago, IL, USA.. Student’s t-test was used for continuous variables. 2 and Fisher’s exact tests were used to analyze categorical variables. Multivariate logistic regression was used to evaluate the association between pre-eclampsia and the various risk factors, while controlling for potential confounders. Adjusted odds ratios ŽORs. were calculated to approximate the relative risk from the regression coefficients, and the associated standard errors were used to determine 95% confidence intervals ŽCIs..
3. Results Four hundred and fifteen of 29 735 women had pre-eclampsia Ž1.4%.. Tables 1 and 2 demonstrate selected demographic characteristics and perinatal outcomes of the study population, respectively. The mean maternal age at delivery and prepregnancy weight were significantly higher in women with pre-eclampsia than in controls. Furthermore, the frequencies of prepregnancy BMI ) 24.2 kgrm2 , preterm delivery, birth weight - 1500 g, Apgar scores - 7 at 1 and 5 min, cesarean deliv-
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329
Table 1 Demographic characteristics of study populationa Variable
Pre-eclampsia Ž n s 415.
Control cohort Ž n s 29 320.
Pb
Age Žyears. Gravidity Parity Prepregnancy weight Žkg. Prepregnancy body mass index Žkgrm2 . - 19.8 19.8᎐24.2 Žreference . ) 24.2 Education Žyears. -7 7᎐12 Žreference . ) 12
30.8" 4.7 2.4" 1.5 1.6" 0.9 52.5" 17.1
29.9" 4.1 2.3" 1.3 1.7" 0.8 49.5" 12.7
- 0.01 0.33 0.21 - 0.01
80 Ž19.3%. 261 Ž62.9%. 74 Ž17.8%.
9799 Ž33.4%. 17 489 Ž59.6%. 2032 Ž6.9%.
- 0.01 ) 0.999 - 0.01
40 Ž9.6%. 359 Ž86.5%. 16 Ž3.9%.
2214 Ž7.6%. 25 917 Ž88.4%. 1189 Ž4.1%.
0.11 ) 0.999 0.91
a b
Data are presented as mean " standard deviation or n Ž%.. P-value based on 2-test for categorical variables and Student’s t-test for continuous ones.
ery, neonatal intensive care unit transfer, neonatal death and abruptio placenta were also statistically higher in women with pre-eclampsia. Table 3 compares the frequency of different potential determinants in pre-eclampsia and the control cohort. Women with pre-eclampsia had a higher frequency of age ) 34 years, nulliparity, a prepregnancy BMI ) 24.2 kgrm2 , having worked during pregnancy, multiple gestation, undergoing assisted reproductive techniques, having a history of pre-eclampsia, overt or gestational diabetes, urinary tract infection during pregnancy and uterine fibroids. On the other hand, a prepregnancy BMI - 19.8 kgrm2 was found to be inversely related to the occurrence of pre-eclampsia. The result of multivariate logistic regression with adjustment for the confounding effect of the above determinants significant by univariate analysis is shown in Table 4. Women who had a history of pre-eclampsia ŽOR 6.3, 95% CI 4.4, 9.2., multiple gestation ŽOR 3.6, 95% CI 2.4, 5.5., a prepregnancy BMI ) 24.2 kgrm2 ŽOR 2.4, 95% CI 1.8, 3.1., were ) 34 years of age ŽOR 1.8, 95% CI 1.4, 2.4., nulliparous ŽOR 1.3, 95% CI 1.2,1.5., had urinary tract infection ŽOR 4.8, 95% CI 1.5, 15.8., or having worked during pregnancy ŽOR 1.9, 95% CI 1.4, 2.4. had an increased risk for pre-eclampsia. On the other hand, a low prepreg-
nancy BMI Ž- 19.8 kgrm2 . was found to be protective against the development of pre-eclampsia ŽOR 0.6, 95% CI 0.4, 0.7..
4. Discussion To our knowledge, this is the largest retrospective cohort study of the risk factors for preeclampsia in an Asian population. The strengths of this study were the use of patient interview and medical record data and the ability to control for possible confounding factors, which enabled an objective investigation into the influence of different risk factors for pre-eclampsia. The prevalence of pre-eclampsia in our institution is 1.4%, which is lower than that of previous reports from mostly non-Asian women w3᎐5,11,12,18x. This finding indicates that preeclampsia might be a relatively uncommon disease in Taiwan, because of our adaptation to universal diagnostic criteria, a weekly chart review, and the case concentration effort of our hospital, which is a referral medical center in Northern Taiwan. Therefore, the frequency of pre-eclampsia in our general population would be even lower. The reason for this disparity remains unknown; however, we believe that a difference
330
C.-J. Lee et al. r International Journal of Gynecology & Obstetrics 70 (2000) 327᎐333
Table 2 Perinatal outcome of pre-eclampsiaa Variable
Pre-eclampsia Control cohort Pb Ž n s 415. Ž n s 29 320.
Preterm delivery Yes 172 Ž41.4%. No 243 Ž58.6%. Birth weight less than 1500 g Yes 50 Ž12.0%. No 365 Ž88.0%. 1-min Apgar score - 7 Yes 78 Ž18.8%. No 337 Ž81.2%. 5-min Apgar score - 7 Yes 29 Ž7.0%. No 386 Ž93.0%. Cesarean delivery Yes 315 Ž75.9%. No 100 Ž24.1%. NICU transfer Yes 110 Ž26.5%. No 305 Ž73.5%. Fetal death Yes 5 Ž1.2%. No 410 Ž98.8%. Neonatal death Yes 12 Ž2.9%. No 403 Ž97.1%. Postpartum hemorrhage Yes 30 Ž7.2%. No 385 Ž92.8%. Abruptio placenta Yes 21 Ž5.1%. No 394 Ž94.9%. Placenta previa Yes 9 Ž2.2%. No 406 Ž97.8%.
2007 Ž6.8%. - 0.01 27 313 Ž93.2%.
345 Ž1.2%. - 0.01 28 975 Ž98.8%. 833 Ž2.8%. - 0.01 28 487 Ž97.2%. 405 Ž1.4%. - 0.01 28 915 Ž98.6%. 11 167 Ž38.1%. - 0.01 18 153 Ž61.9%. 1308 Ž4.5%. - 0.01 28 012 Ž95.5%. 170 Ž0.6%. 29 150 Ž99.4%.
0.10
94 Ž0.3%. - 0.01 29 226 Ž99.7%. 2007 Ž6.8%. 27 313 Ž93.2%.
0.77
271 Ž0.9%. - 0.01 29 049 Ž99.1%. 321 Ž1.1%. 28 999 Ž98.9%.
0.05
a Abbre¨ iation: NICUs neonatal intensive care unit. Data are presented as n Ž%.. b P-values based on 2-tests.
in the prevalence of variable risk factors for preeclampsia Ži.e. less prepregnancy obese, and more underweight women. between different ethnicities may partially contribute to this discrepancy, in addition to other environmental or genetic effects. Consistent with previous reports w4᎐6,8,14x, we found that obese women, defined as having a prepregnancy BMI ) 24.2 kgrm2 in this study, carried an increased risk of developing pre-
eclampsia. Furthermore, a prepregnancy BMI 19.8 kgrm2 was found to be protective against the disease. Eskenazi et al. w14x had demonstrated a similar result, but the protective effect of prepregnancy underweight did not reach statistical significance, possibly due to limited samples in their study. It has been observed that obese women were more likely to have increased levels of serum triglycerides, very low-density lipoproteins, and formation of small, dense low-density lipoprotein particles w19x. A similar lipid profile has also been found in women with pre-eclampsia w20x. Such lipid alterations have been suggested to promote oxidative stress, caused by either ischemia-reperfusion mechanism or activated neutrophils, and lead to endothelial cell dysfunction w1,21x. Unlike previous reports w14,15x, we found that women) 34 years of age were at increased risk of pre-eclampsia, even when excluding those with chronic hypertension. Such an association may be related to the progressive vascular endothelial damage that occurs with aging. Naeye w22x reported that, in a series of 62 autopsies, the incidence of sclerotic lesions in myometrial arteries increased with aging, from 11% at age 17᎐19 years to 61% at age 30᎐39 years, and 83% after age 39. Obstruction of the maternal spiral arteriolar lumina by atherosis has been frequently observed in pregnancies complicated by preeclampsia w23x. Therefore, we believe women at an advanced age should be followed carefully for the possible development of pre-eclampsia. Our observation confirmed most previous studies that nulliparity, multiple gestations and a history of pre-eclampsia were significant risk factors for pre-eclampsia, consistent with the hypothesis that immune maladaptation might play a role in triggering the development of pre-eclampsia w1x. Nevertheless, we did not demonstrate that having a previous history of abortion protected against pre-eclampsia. A minor limitation of the present study is the inability to differentiate between spontaneous and induced abortion because of the lack of information on this variable. Some workers w14x suggested previously that a history of spontaneous abortion, which usually occurs later in gestation than therapeutic abortions, provided
C.-J. Lee et al. r International Journal of Gynecology & Obstetrics 70 (2000) 327᎐333
protection against pre-eclampsia. In pre-eclamptic pregnancies, there is failure of the second wave of trophoblastic invasion in the second trimester ex-
331
tending into the inner one-third of the myometrium. We hypothesized that if an abortion occurs beyond the critical point of triggering the
Table 3 Potential determinants of pre-eclampsiaa Potential determinant
Age Žyears. - 20 20᎐34 Žreference . ) 34 Nulliparous Yes No Prepregnancy body mass index Žkgrm2 . - 19.8 19.8᎐24.2 Žreference . ) 24.2 Education Žyears. -7 7᎐12 Žreference . ) 12 Unmarried Yes No Worked during pregnancy Yes No Multiple gestation Yes No Conception assisted by reproductive techniques Yes No Fetal male gender Yes No History of abortion Yes No History of fetal death Yes No History of pre-eclampsiac Yes No Overt diabetes Yes No Gestational diabetes Yes No
Pre-eclampsia Ž n s 415.
Control cohort Ž n s 29 320.
Pb
2 Ž0.5%. 321 Ž77.3%. 92 Ž22.2%.
201 Ž0.7%. 25 367 Ž86.5%. 3752 Ž12.8%.
0.73 ) 0.999 - 0.01
245 Ž59.0%. 170 Ž41.0%.
14 576 Ž49.7%. 14 744 Ž50.3%.
- 0.01
80 Ž19.3%. 261 Ž62.9%. 74 Ž17.8%.
9799 Ž33.4%. 17 489 Ž59.6%. 2032 Ž6.9%.
- 0.01 ) 0.999 - 0.01
40 Ž9.6%. 359 Ž86.5%. 16 Ž3.9%.
2214 Ž7.6%. 25 917 Ž88.4%. 1189 Ž4.1%.
0.11 ) 0.999 0.91
2 Ž0.5%. 413 Ž99.5%.
109 Ž0.4%. 29 211 Ž99.6%.
0.67
353 Ž85.1%. 62 Ž14.9%.
21 043 Ž71.8%. 8277 Ž28.2%.
- 0.01
34 Ž8.2%. 381 Ž91.8%.
514 Ž1.8%. 28 806 Ž98.2%.
- 0.01
14 Ž3.4%. 401 Ž96.6%.
357 Ž1.2%. 28 963 Ž98.8%.
- 0.01
204 Ž49.2%. 211 Ž50.8%.
15 527 Ž53.0%. 13 793 Ž47.0%.
0.13
188 Ž45.3%. 227 Ž54.7%.
12 684 Ž43.3%. 16 636 Ž56.7%.
0.43
10 Ž2.4%. 405 Ž97.6%.
302 Ž1.0%. 29 018 Ž99.0%.
- 0.05
19 Ž11.2%. 151 Ž88.8%.
242 Ž1.6%. 14 502 Ž98.4%.
- 0.01
3 Ž0.7%. 412 Ž99.3%.
55 Ž0.2%. 29 265 Ž99.8%.
- 0.05
33 Ž8.0%. 382 Ž92.0%.
1376 Ž4.7%. 27 944 Ž95.3%.
- 0.01
C.-J. Lee et al. r International Journal of Gynecology & Obstetrics 70 (2000) 327᎐333
332 Table 3 Ž Continued. Potential determinant
Urinary tract infection during pregnancy Yes No Uterine fibroids Yes No
Pre-eclampsia Ž n s 415.
Control cohort Ž n s 29 320.
Pb
3 Ž0.7%. 412 Ž99.3%.
50 Ž0.2%. 29 270 Ž99.8%.
- 0.05
8 Ž1.9%. 407 Ž98.1%.
195 Ž0.7%. 29 125 Ž99.3%.
- 0.01
a
Data are presented as n Ž%.. P-values based on 2-tests for categorical variables and Student’s t-test for continuous ones. c Only includes those women who had given birth previously. b
immune mechanisms involved in the etiology of pre-eclampsia, it can provide some protection against the disease. Therefore, a mixture of induced and spontaneous abortions will inevitably mask the protective effect of an abortion at late gestation. Further investigations regarding the association of abortions at different gestation and pre-eclampsia are needed in order to test the above hypotheses. Although we have found that urinary tract infection and working during pregnancy were significantly associated with pre-eclampsia, another limitation of this study is that diagnosis of urinary tract infection was not exclusively confirmed by urine culture, and information about the length of employment during pregnancy was not consistently provided on the medical chart and, thereTable 4 Results of multivariate logistic regression a
References
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6.3 3.6 2.4
4.4, 9.2 2.4, 5.5 1.8, 3.1
1.8 1.3 4.8
1.4, 2.4 1.2, 1.5 1.5, 15.8
1.9 0.6
1.4, 2.4 0.4, 0.7
a
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