Risk factors of early and late onset pre-eclampsia

Adisorn Aksornphusitaphong and Vorapong PhupongDepartment of Obstetrics and Gynecology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand

Abstract

Aims: The aim of this study was to identify the differences in risk factors between early and late onsetpre-eclampsia.Material and Methods: A casecontrol study was carried out involving pregnancies with pre-eclampsia (152early onset and 297 late onset) and 449 controls at King Chulalongkorn Memorial Hospital, Bangkok, Thailandbetween 1 January 2005 and 31 December 2010. The data were reviewed from antenatal and delivery records.Results: Factors which were significantly associated with increased risk for both early and late onset pre-eclampsia were family history of diabetes mellitus, high pre-pregnancy body mass index 25 kg/m2 andweight gain 0.5 kg per week. History of chronic hypertension (odds ratio 4.4; 95% confidence interval2.19.3) was significantly associated with increased risk for only early onset pre-eclampsia, while family historyof chronic hypertension (odds ratio 18; 95% confidence interval 654) was significantly associated withincreased risk for only late onset pre-eclampsia.Conclusions: The risk factors that differ between early and late onset of pre-eclampsia were history of chronichypertension and family history of chronic hypertension. Family history of diabetes mellitus, pre-pregnancybody mass index 25 kg/m2 and weight gain 0.5 kg per week were risk factors of both early and late onsetpre-eclampsia. These risk factors are of value to obstetricians in identifying patients at risk for pre-eclampsiaand in implementing primary prevention.Key words: early onset, late onset, pre-eclampsia, risk factor, Thai.

Introduction

Pre-eclampsia is a common obstetric complication. It isone of three common causes of maternal mortality inthe world.1 In severe cases, it causes multiple organfailures, which leads to maternal death. A high fetalmorbidity and mortality rate is associated with prema-turity, placental insufficiency and intrauterine growthrestriction (IUGR), which result from this disorder.2,3

The exact cause of pre-eclampsia is still unknown. Theimpaired placentation is one possible cause.4

There are many studies that aim to evaluate riskfactors of pre-eclampsia. Primigravida, previouspregnancy-induced hypertension, obesity, diabetes,hypertension and multiplicity are risk factors. Some

factors are protective; one of these is cigarette smok-ing.5 Some studies demonstrated higher morbidity andmortality from pre-eclampsia at an early gestationalage than from that at a late stage.2,68 The early onset ofthis disorder causes severe morbidity in mothers and ahigher preterm birth rate in fetuses.7,9

The aim of this study is to find the difference inrisk factors between early onset and late onset pre-eclampsia in the Thai population.

Methods

This was a casecontrol study conducted at the Depart-ment of Obstetrics and Gynecology, King Chula-longkorn Memorial Hospital, Faculty of Medicine,

Received: February 1 2012.Accepted: July 20 2012.Reprint request to: Dr Vorapong Phupong, Department of Obstetrics and Gynecology, Faculty of Medicine, ChulalongkornUniversity, Rama IV Road, Pathumwan, Bangkok 10330, Thailand. Email: vorapong.p@chula.ac.th

bs_bs_banner

doi:10.1111/j.1447-0756.2012.02010.x J. Obstet. Gynaecol. Res. Vol. 39, No. 3: 627631, March 2013

2012 The Authors 627Journal of Obstetrics and Gynaecology Research 2012 Japan Society of Obstetrics and Gynecology

Chulalongkorn University, Bangkok, Thailand. Thestudy was approved by the Institutional Review Boardof the Faculty of Medicine, Chulalongkorn University.

The antenatal and delivery records of all pregnantwomen with gestational age of 20 weeks or more andestimate fetal weight of500 g delivered (regardless oflive birth or stillbirth) at King Chulalongkorn Memo-rial Hospital from 1 January 2005 to 31 December 2010were reviewed. Exclusion criteria included abortion,hydatidiform mole, pregnancies complicated withchromosomal or structural anomalies and birth beforearrival.

Data were divided into three groups (two casegroups and one control group). Cases were diagnosedas mild pre-eclampsia, severe pre-eclampsia, eclamp-sia, or superimposed pre-eclampsia. Cases weredivided into two subgroups, early onset and late onset.Controls were normotensive pregnant women whodelivered consecutively after pre-eclamptic pregnantwomen.

Data were collected regarding general information,pregnancy information, antenatal care, medical history,and pregnancy outcome.

Mild pre-eclampsia was defined as a blood pressureof at least 140/90 mmHg, measured on two occasionsat least 6 h apart, with proteinuria of at least 300 mg/24 h or at least 1+ on urine dipstick test. Both elevatedblood pressure and proteinuria occurred for the firsttime after gestational age of 20 weeks.10 Severe pre-eclampsia was defined on the basis of pre-eclampsiawith one or more of the following: blood pressure of atleast 160/110 mmHg, proteinuria of at least 5 g/24 h orat least 3+ on urine dipstick test, serum creatinine>1.2 mg/dL, platelet count

significantly higher in the early onset pre-eclampsiagroup than in controls. The pregestational weight andweight gain per week were significantly higher in boththe early and late onset pre-eclampsia groups than incontrols. The total weight gain was significantly higherin the late onset pre-eclampsia group than in controls.

Perinatal characteristics are shown in Table 2. Theproportion of preterm deliveries and cesarean sectionswere significantly higher in both the early and lateonset pre-eclampsia groups than in controls. Thecontrol group did not represent a normal population inour institution. The preterm birth rate appeared to behigh in the controls. The reasons for this may be asfollows: (i) our institution is a tertiary care hospital,and thus, there were a high number of complicatedcases that needed preterm delivery; and (ii) coinciden-tally, controls were recruited from normotensivepregnant women who delivered consecutively afterpre-eclamptic pregnant women. The proportion ofApgar scores below 7 at 1 and 5 min were significantlyhigher in the early onset pre-eclampsia group than incontrols. Neonatal birthweight in the early onset pre-eclampsia group was significantly less than in controls.

From univariate analysis, maternal age 35 years,pre-pregnancy BMI 2529.9 kg/m2, weightgain 0.5 kg per week, female infant, calcium intake,family history of diabetes mellitus (DM), and family

history of hypertension were significantly associatedwith increased risk of both early and late onset pre-eclampsia. Multiparity, chronic hypertension, pregesta-tional DM or gestational DM, history of pre-eclampsiain previous pregnancy, history of hemolysis, andelevated liver enzyme and low platelet (HELLP) inprevious pregnancy were significantly associatedwith increased risk of early onset pre-eclampsia only.There was no risk factor significantly associated withincreased risk of late onset pre-eclampsia only. Gesta-tional age at first antenatal care 27 weeks andpre-pregnancy BMI < 20 kg/m2 were significantlyassociated with decreased risk of both early and lateonset pre-eclampsia. Gestational age at first antenatalcare 1426 weeks and maternal weight gain < 0.2 kgper week were significantly associated with decreasedrisk of late onset pre-eclampsia only.

Table 3 shows the results of multivariate logisticregression analysis. Risk factors which were signifi-cantly associated with increased risk of both early andlate onset pre-eclampsia were family history of DM,pre-pregnancy BMI 2529.9 kg/m2, pre-pregnancyBMI 30 kg/m2 and weight gain 0.5 kg per week.History of chronic hypertension (OR 4.4; 95% CI 2.19.3) was significantly associated with increased riskof early onset pre-eclampsia only. Family historyof chronic hypertension (OR 18; 95% CI 654) was

Table 1 Demographic characteristics of study population

Characteristic Control(n = 449)

Early onset(n = 152)

P-value Late onset(n = 297)

P-value

Age (years) 28.5 6.6 31.6 6.4

significantly associated with increased risk of late onsetpre-eclampsia only. Pre-pregnancy BMI < 20 kg/m2

was a significant protective factor for both early andlate onset pre-eclampsia. Maternal weight gain < 0.2 kgper week was a significant protective factor for earlyonset pre-eclampsia only.

Discussion

This study shows that risk factors that differ betweenearly and late onset pre-eclampsia were a history ofchronic hypertension and family history of chronichypertension. History of chronic hypertension wassignificantly associated with increased risk of earlyonset pre-eclampsia only, while family history ofchronic hypertension was significantly associated withincreased risk of late onset pre-eclampsia only.

There has been only one study evaluating the riskfactors of early and late onset of pre-eclampsia.12 Fanget al. did not find any difference in risk factors betweenearly and late onset pre-eclampsia.12 This may be due tothe small sample size of their study. There were only 29cases of early onset and 121 cases of late onset pre-eclampsia. They found that pre-pregnancy body massindex >30 kg/m2 and failure to use prenatal careservices were associated with increased risk of pre-eclampsia.12 The difference between this study and thatof Fang et al. may be due to the difference of method-ology. This study recruited cases as early and late onsetpre-eclampsia at the beginning of the study, whileFang et al. divided cases into early and late onsetpre-eclampsia by subgroup analysis.

Poon et al.13 developed prediction algorithms forhypertensive disorders based on multivariate analysisof factors from the maternal history and compared theestimated performance of such algorithms in the pre-diction of early pre-eclampsia, late pre-eclampsia and

gestational hypertension. There were 37 cases withearly pre-eclampsia, 128 with late pre-eclampsia,and 140 with gestational hypertension. They foundthat predictors of early pre-eclampsia were Africanrace, chronic hypertension, prior pre-eclampsia anduse of ovulation drugs. Predictors of late onsetpre-eclampsia and gestational hypertension wereincreased maternal age and BMI, and family historyor history of pre-eclampsia. The detection rates ofearly pre-eclampsia, late pre-eclampsia and gesta-tional hypertension in screening by maternal factorswere only 37.0, 28.9 and 20.7%, respectively, for a 5%false positive rate.

Nanjundan et al. evaluated risk factors for early onsetsevere pre-eclampsia and eclampsia.14 They found thathistory of pre-eclampsia or eclampsia in a previouspregnancy, exposure to passive smoking, inadequateantenatal supervision, family history of hypertension inone or more first-degree relatives, living in a jointfamily, being overweight and lower socioeconomicstatus were associated with increased risk of earlyonset pre-eclampsia and eclampsia. The difference inthese studies may be due to difference in the studypopulation.

The results of the present study were similar to pre-vious studies.6,7,11 Overweight and obesity increasedthe risk of pre-eclampsia, which was explained byincrease in triglyceride and free fatty acid levels. Theselipid alterations can produce major factors leading toendothelial cell dysfunction in pre-eclampsia withincreased circulating levels of lipid peroxides oxidativestress. This can lead to endothelial cell damage.1517

Maternal weight gain < 0.2 kg per week was a signifi-cant protective factor for early onset pre-eclampsia.Pre-pregnancy BMI < 20 kg/m2 was a significantprotective factor for late onset pre-eclampsia. This issimilar to the previous studies.11,18

Table 3 Results of multivariate logistic regression analysis

Risk factors Early onset Late onsetAdjustedOR (95% CI)

AdjustedOR (95% CI)

History of chronic hypertension 4.4 (2.1, 9.3) Family history of hypertension 18 (6, 54)Family history of diabetes 2.5 (1.1, 5.6) 2.7 (1.6, 4.4)Pre-pregnancy body mass index 2529.9 kg/m2 3.5 (1.3, 8.9) 2.1 (1.2, 3.7)Pre-pregnancy body mass index 30 kg/m2 16.2 (4.5, 58.3) 5.8 (2.8, 11.9)Pre-pregnancy body mass index < 20 kg/m2 0.5 (0.3, 0.8)Weight gain < 0.2 kg/week 0.3 (0.1, 0.9) Weight gain 0.5 kg/week 2.1 (1.2, 3.7) 1.9 (1.3, 2.8)

CI, confidence interval; OR, odds ratio.

A. Aksornphusitaphong and V. Phupong

630 2012 The AuthorsJournal of Obstetrics and Gynaecology Research 2012 Japan Society of Obstetrics and Gynecology

History of chronic hypertension was a significantrisk factor for early onset pre-eclampsia in the presentstudy. This is in agreement with previous studies thatshowed that chronic hypertension was a risk factor forpre-eclampsia.8,18 Family history of chronic hyperten-sion was a significant risk factor for late onset pre-eclampsia in the present study. This is in agreementwith previous studies.19,20

In contrast to previous studies,2,6,8 cigarette smokingand high calcium intake were not protective factors inour study. This may due to the relatively small numberof cigarette smokers in the groups and because peoplein Thailand generally take a sufficient amount ofcalcium. However, we did not exactly evaluate thecalcium intake in their food. We did not identify mater-nal age as a significant risk factor for early and lateonset pre-eclampsia. This is consistent with previousstudies.14,21

Chronic hypertension can cause end-organ damageand vascular complications. This may be the reasonwhy chronic hypertension is associated with earlyonset pre-eclampsia; however, family history ofchronic hypertension is associated with late onset pre-eclampsia. This may be explained by a genetic predis-position. Vascular complications still do not occur inthese cases.

The strength of the present study was the largenumber of cases in early and late onset pre-eclampsia.Thus, we could compare and indentify the difference inthe risk factors between these groups. The limitation ofthis study was the small number of smokers and thesmall number of pregnant women who used calciummedication during pregnancy. Thus we could notassess the effect of these factors.

In conclusion, the risk factors differing betweenearly and late onset pre-eclampsia were history ofchronic hypertension and family history of chronichypertension. Family history of DM, pre-pregnancyBMI 25 kg/m2 and weight gain 0.5 kg per weekwere risk factors of both early and late onset pre-eclampsia. These risk factors are valuable to obstetri-cians for identifying patients at risk for pre-eclampsiaand for implementing primary prevention.

Disclosure

No author has any potential conflict of interest.

References

1. World Health Organization. Maternal mortality fact sheet.2008.

2. Assis TR, Viana FP, Rassi S. Study on the major maternal riskfactors in hypertensive syndromes. Arq Bras Cardiol 2008; 91:1117.

3. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365: 785799.

4. Phupong V, Dejthevaporn T. Predicting risks of preeclampsiaand small for gestational age infant by uterine artery Doppler.Hypertens Pregnancy 2008; 27: 387395.

5. Bainbridge SA, Sidle EH, Smith GN. Direct placental effectsof cigarette smoke protect women from pre-eclampsia: Thespecific roles of carbon monoxide and antioxidant systems inthe placenta. Med Hypotheses 2005; 64: 1727.

6. Duckitt K, Harrington D. Risk factors for pre-eclampsia atantenatal booking: Systematic review of controlled studies.BMJ 2005; 330: 565571.

7. Hernandez-Diaz S, Toh S, Cnattingius S. Risk of pre-eclampsia in first and subsequent pregnancies: Prospectivecohort study. BMJ 2009; 338: b2255.

8. Conde-Agudelo A, Belizan JM. Risk factors for pre-eclampsiain a large cohort of Latin American and Caribbean women.BJOG 2000; 107: 7583.

9. Mattar F, Sibai BM. Eclampsia. VIII. Risk factors for maternalmorbidity. Am J Obstet Gynecol 2000; 182: 307312.

10. ACOG. Diagnosis and management of preeclampsia andeclampsia. ACOG practical bulletin. Clinical managementguidelines for obstetrician-gynecologists Number 33, January2002. Obstet Gynecol 2002; 99: 159166.

11. Luealon P, Phupong V. Risk factors of preeclampsia in Thaiwomen. J Med Assoc Thai 2010; 93: 661666.

12. Fang R, Dawson A, Lohsoonthorn V, Williams MA. Riskfactors of early and late onset preeclampsia among Thaiwomen. Asian Biomed (Res Rev News) 2009; 3: 477486.

13. Poon LC, Kametas NA, Chelemen T, Leal A, Nicolaides KH.Maternal risk factors for hypertensive disorders in pregnancy:A multivariate approach. J Hum Hypertens 2010; 24: 104110.

14. Nanjundan P, Bagga R, Kalra JK, Thakur JS, Raveendran A.Risk factors for early onset severe pre-eclampsia and eclamp-sia among north Indian women. J Obstet Gynaecol 2011; 31:384389.

15. Takacs P, Kauma SW, Sholley MM, Walsh SW, Dinsmoor MJ,Green K. Increased circulating lipid peroxides in severepreeclampsia activate NF-kappaB and upregulate ICAM-1 invascular endothelial cells. FASEB J 2001; 15: 279281.

16. OBrien TE, Ray JG, Chan WS. Maternal body mass index andthe risk of preeclampsia: A systematic overview. Epidemiology2003; 14: 368374.

17. Cheng MH, Wang PH. Placentation abnormalities in thepathophysiology of preeclampsia. Expert Rev Mol Diagn 2009;9: 3749.

18. Lee CJ, Hsieh TT, Chiu TH, Chen KC, Lo LM, Hung TH. Riskfactors for pre-eclampsia in an Asian population. Int J Gynae-col Obstet 2000; 70: 327333.

19. Roes EM, Sieben R, Raijmakers MT, Peters WH, Steegers EA.Severe preeclampsia is associated with a positive familyhistory of hypertension and hypercholesterolemia. HypertensPregnancy 2005; 24: 259271.

20. Qiu C, Williams MA, Leisenring WM et al. Family history ofhypertension and type 2 diabetes in relation to preeclampsiarisk. Hypertension 2003; 41: 408413.

21. Eskenazi B, Fenster L, Sidney S. A multivariate analysis of riskfactors for preeclampsia. JAMA 1991; 266: 237241.

Early and late onset pre-eclampsia

2012 The Authors 631Journal of Obstetrics and Gynaecology Research 2012 Japan Society of Obstetrics and Gynecology