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Early onset preeclampsia in subsequent pregnancies correlates with early onset preeclampsia in first pregnancy
European Journal of Obstetrics & Gynecology and Reproductive Biology 177 (2014) 94–99
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European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Early onset preeclampsia in subsequent pregnancies correlates with early onset preeclampsia in first pregnancy X.L. Li a, T.T. Chen a, X. Dong a, W.L. Gou a, S. Lau b, P. Stone b, Q. Chen b,c,* a
Department of Obstetrics & Gynaecology, First affiliated Hospital of Xi’an Jiaotong University, Xi’an, China Department of Obstetrics & Gynaecology, The University of Auckland, Auckland, New Zealand c The Hospital of Obstetrics & Gynaecology, Fudan University, Shanghai, China b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 12 December 2013 Received in revised form 13 March 2014 Accepted 31 March 2014
Objective: Preeclampsia is a major complication of pregnancy and its occurrence in a first pregnancy is a major risk factor for recurrence in subsequent pregnancies. Whether the time of onset or the severity of preeclampsia in a first pregnancy is associated with the incidence of recurrent preeclampsia is not clear. We performed a retrospective study to analyse the incidence of recurrent preeclampsia and associations of the time of onset and the severity of preeclampsia between first preeclampsia and recurrent preeclampsia. Study design: Ninety-two women with previous preeclampsia who had a second pregnancy in a 4 year period were included. Data on the first and second pregnancies were obtained and included maternal age, maternal height and weight, gestation week at onset of preeclampsia and at delivery, blood pressure, proteinuria, interval between pregnancies and birth weights. Results: Fifty-five women with previous preeclampsia developed recurrent preeclampsia (59.8%). The difference in the incidence of recurrent early and late onset preeclampsia was not significant different (65.3% versus 53.4%, p > 0.05). The difference in the incidence of mild or severe disease in those who experienced recurrent preeclampsia was also not significant (59.6% versus 60%, p > 0.05). The severity of preeclampsia in second pregnancy was not associated with the severity of preeclampsia in first pregnancy. However 93.7% women with previous early onset preeclampsia developed early onset preeclampsia in second pregnancy and 56.5% women with previous late onset preeclampsia developed early onset preeclampsia in second pregnancy. In addition, 76.2% women with previous mild preeclampsia developed severe preeclampsia in second pregnancy. The baby weight in recurrent preeclampsia was significantly decreased compared to that in first pregnancy with preeclampsia. Conclusion: Our data demonstrate that there was no association between the incidence of recurrent preeclampsia and the time of onset or severity of preeclampsia in first pregnancy. But our data here may suggest that women with early onset preeclampsia in first pregnancy are more likely to experience early onset preeclampsia in second pregnancy. The severity of recurrent preeclampsia is increased regardless the severity in first pregnancy. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Recurrent preeclampsia Time of onset Severity Preeclampsia China
Introduction Preeclampsia is a placental specific disorder that becomes clinically apparent after 20 weeks of gestation or within the first 4– 6 weeks postpartum. Preeclampsia can affect both the mother and the unborn baby and is estimated to affect between 5 and 8% of
* Corresponding author at: 419 Fang Xie Road, The Hospital of Obstetrics & Gynaecology, Fudan University, Shanghai, China. Tel.: +86 13611691734/+64 992 35645; fax: +86 21 63455090. E-mail address: [email protected] (Q. Chen). http://dx.doi.org/10.1016/j.ejogrb.2014.03.043 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.
healthy pregnancies [1]. It is responsible for about 76,000 maternal deaths and 500,000 infant deaths per year [2]. The clinical symptoms and signs of preeclampsia are high blood pressure, proteinuria, sudden weight gain, headaches, swelling and blurred vision and risk of eclampsia in addition to fetal complications including growth restriction and stillbirth. Although the pathogenesis of preeclampsia is not fully understood, it is widely accepted that both maternal and placental factors contribute to the pathogenesis of this disease. It is primarily a disease of endothelial activation, inflammation, vasoconstriction and multi-organ damage. Maternal risk factors at antenatal include maternal age, parity, previous preeclampsia, multiple pregnancy, body mass index (BMI) and pre-existing
X.L. Li et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 177 (2014) 94–99
medical conditions such as antiphospholipid antibodies syndromes [3], and chronic hypertension or renal disease. Of these risk factors, women with previous preeclampsia, particularly if the onset had been before the third trimester have seven times the risk of developing preeclampsia in a second pregnancy suggesting previous preeclampsia is the single largest risk factor for developing recurrent preeclampsia [4]. Although there are not many studies looking at the incidence of recurrent preeclampsia in subsequent pregnancies, studies showed that the incidence of recurrent preeclampsia is around 13 to 65% depending on the time of onset and the severity of preeclampsia in the first pregnancy [5–7]. It has also been suggested that there are geographical variations in incidence of preeclampsia [5–7]. To reduce the risk of recurrent preeclampsia, there is growing evidence suggesting that low dose aspirin, calcium or possibly folic acid supplementation may have some benefits for women who suffered preeclampsia in a previous pregnancy. Most previous studies have focused on the incidence of recurrent preeclampsia and potential risk factors for this in subsequent pregnancies in women with a prior history of the condition [3,4,8,9]. Whether the time of onset or the severity of preeclampsia in first pregnancy is associated with the incidence of recurrent preeclampsia is far from clear. In addition, only a few studies have compared women with previous preeclampsia who developed recurrent preeclampsia with who did not develop recurrent preeclampsia. China instituted a ‘‘one child policy’’ at the end of the 1970s, however after 30 years of strict enforcement, recently it has become apparent that there has been relaxation in the application of that policy. Therefore we undertook this study to analyse the incidence of recurrent preeclampsia in subsequent pregnancies in women with a history of preeclampsia and to define the potential maternal risk factors for recurrent preeclampsia. Material and methods Study population This retrospective study was performed at a university teaching hospital serving a diverse urban and rural population of around 8 million in China. Data on 92 primiparous women with previous preeclampsia was collected from Department of Obstetrics and Gynaecology, First Hospital of Xian, Jiaotong University of China from January 2008 to December 2012. Data recorded included maternal age, maternal height and weight, gestation at presentation of preeclampsia, gestation at delivery, blood pressure on admission, proteinuria, baby weight, interval between two pregnancies (live birth), partner information (whether changed the partners in second pregnancy), and delivery modes in the first and second pregnancies. All women were non-smoking and had no family history of preeclampsia. In the second pregnancy, all patients received treatment with calcium supplementation after 12 weeks gestation. Of the 92 primiparous women, 55 women developed recurrent preeclampsia. Preeclampsia was defined as a maternal systolic blood pressure 140 mmHg and/or diastolic blood pressure 90 mmHg measured on two occasions separated by at least 6 h, and proteinuria >300 mg on a 24 h urinary collection or qualitatively, >1+, after 20 weeks of gestation following the guidelines of the International Society for the Study of Hypertension in Pregnancy (ISSHP) [10]. Maternal systolic blood pressure 160 mmHg and/or diastolic blood pressure 110 mmHg on admission was defined as severe preeclampsia. Early onset preeclampsia was defined as occurring at less than 34 weeks. Body mass index (BMI) was calculated as the ratio of maternal weight and height (kg/m2) at the first booking visit (around 12 weeks of gestation). According to the WHO classification of BMI for Asian/Indian women, the BMI for normal,
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overweight and obese is 18.5–22.9 kg/m2, 23–27.4 kg/m2 and greater than 27.5 kg/m2, respectively. Statistical analysis The statistical differences in maternal age, gestation week at presentation or delivery in the first pregnancy or second pregnancy, and birth weight, and BMI between women with recurrent preeclampsia and without recurrent preeclampsia were assessed by Mann–Whitney U-test using Prism software package. The statistical differences in the incidence of recurrent preeclampsia in relationship to the severity or the time of onset of preeclampsia between recurrent preeclampsia and no recurrent preeclampsia were assessed by a Fisher’s exact test using Prism software. p-Values of <0.05 were considered significant. Results There were 1252 women who developed preeclampsia from January 2008 to December 2012 in the Department of Obstetrics & Gynaecology, First Hospital of Xian, Jiaotong University. Of these, 92 primiparous women with previous preeclampsia had subsequent pregnancies and of these, 55 women developed recurrent preeclampsia. The incidence of recurrent preeclampsia was 59.8%. The general clinical characteristics of the women with previous preeclampsia (n = 92) are summarised in Table 1. In the first Table 1 The clinical characteristics of the women with preeclampsia and recurrent preeclampsia. Women with or without recurrent preeclampsia Recurrent PE (N = 55) Characteristics of the first pregnancy (N = 92) Maternal age (years, median/range) 25 (21–37) Gestation week at presentation 32 (18–41)* Gestation week at delivery 36 (23–41) (median/range) Baby weight (g, median/range) 3073 (1345–3865) Systolic BP (mmHg, median/range) 160 (140–185) Diastolic BP (mmHg, median/range) 100 (90–110) Proteinuria +–+++ Stillbirth 2 (3.6%) Body mass index (BMI) 24.13 (20.32–30.39)* Delivery model Vaginal delivery (number of women) 13 Caesarean section (number of women) 42 Characteristics of the second pregnancy (N = 92) Maternal age (years, median/range) 32 (20–40) Gestation week at presentation 34 (18–41) Gestation week at delivery 35 (24–41)* (median/range) Baby weight (g, median/range) 2778 (1513–3446)#,* Systolic BP (mmHg, median/range) 165 (130–220)* Diastolic BP (mmHg, median/range) 110 (90–140)* Proteinuria +–+++ Stillbirth 2 (3.6%) Body mass index (BMI) 23.53 (19.95–29.14)* Time interval between pregnancies 4 (1–16)* (years) Delivery model Vaginal delivery (number of women) 18 Caesarean section (number of women) 37
No recurrent PE (N = 37) 25 (19–33) 35 (26–42) 36 (32–42) 3201 (2015–3810) 160 (140–200) 100 (90–130) +–+++ 1 (2.7%) 22.04 (19.92–24.13) 5 32 27 (22–36) N/A 39 (36–41) 3276 (2715–3655) 125 (110–135) 75 (65–85) Negative 0 21.63 (19.72–25.15) 3 (1–6)
3 34
* p < 0.05, Women who developed recurrent preeclampsia versus women who did not develop recurrent preeclampsia. # p = 0.03, baby weight in first pregnancy versus in second pregnancy in women who developed recurrent preeclampsia.
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pregnancy, the median maternal age in 55 primiparous women who developed recurrent preeclampsia was 25 years old (range 21 to 37 years). The median gestation at presentation was 32 weeks (range18 to 41 weeks). The median baby weight was 3073 g (range 1345 to 3865 g). In the 37 primiparous women who did not develop recurrent preeclampsia, the median maternal age was 25 years old (range 19 to 33 years). The median gestation at presentation was 35 weeks (range 26 to 42 weeks). The median baby weight was 3201 g (range 2015 to 3810 g). There was no significant difference in maternal age, gestation at delivery, baby weight and blood pressure on admission in first pregnancy between women who did or did not develop recurrent preeclampsia. However preeclampsia presented significantly earlier in the first pregnancy in those who developed recurrent disease than those who did not have preeclampsia in the subsequent pregnancy (32 versus 35 weeks, p = 0.017). In addition, the BMI in first pregnancy in women who developed recurrent preeclampsia was significant higher than that in women who did not develop recurrent preeclampsia (24.13 versus 22.04, p = 0.001). In the second pregnancy, the gestation weeks at delivery and birth weight were significantly lower in women who developed recurrent preeclampsia than in women who did not (p = 0.001). The BMI in women who developed recurrent preeclampsia was
significantly higher than in those women who did not develop recurrent preeclampsia (p = 0.001). The median interval between pregnancies (live birth) in women who developed recurrent preeclampsia was significantly longer than that in women who did not develop recurrent preeclampsia (4 years versus 3 years, p = 0.005) (Table 1). When we divided 92 women with previous preeclampsia by the time of onset in first pregnancy, 49 women developed early onset preeclampsia and 43 women developed late onset preeclampsia. When we divided 92 women with previous preeclampsia by the severity of preeclampsia in first pregnancy, 57 women developed severe preeclampsia and 35 women developed mild preeclampsia divided in first pregnancy. We analysed whether the time of onset or the severity of preeclampsia in first pregnancy was associated with the incidence of recurrent preeclampsia. Thirty two out of 49 (65.3%) women with previous early onset preeclampsia developed recurrent preeclampsia and 23 out of 43 (53.4%) women with previous late onset preeclampsia developed recurrent preeclampsia. Thirty four out of 57 (59.6%) women with previous severe preeclampsia developed recurrent preeclampsia and 21 out of 35 (60%) women with previous mild preeclampsia developed recurrent preeclampsia. There was no significant association of incidence of recurrent
[(Fig._1)TD$IG] A Early onset preeclampsia in first pregnancy (N=49)
Recurrent Preeclampsia (N=32, 65.3%)
Early Onset Recurrent Preeclampsia (N=30, 93.7%)
NO Recurrent Preeclampsia (N=17, 34.7%)
Late onset Recurrent Preeclampsia (N=2, 6.3%)
Late onset preeclampsia in first pregnancy (N=43)
Recurrent Preeclampsia (N=23, 53.4%)
Early Onset Recurrent Preeclampsia (N=13, 56.5%)
NO Recurrent Preeclampsia (N=20, 46.6%)
Late onset Recurrent Preeclampsia (N=10, 43.5%)
B Severe preeclampsia in first pregnancy (N=57)
Recurrent Preeclampsia (N=34, 59.6%)
Severe Recurrent Preeclampsia (N=25, 73.5%)
NO Recurrent Preeclampsia (N=23, 40.4%)
Mild Recurrent Preeclampsia (N=9, 26.5%)
Mild preeclampsia in first pregnancy (N=35)
Recurrent Preeclampsia (N=21, 60.0%)
Severe Recurrent Preeclampsia (N=16, 76.2%)
NO Recurrent Preeclampsia (N=14, 40%)
Mild Recurrent Preeclampsia (N=5, 23.8%)
Fig. 1. Flow diagram showing the incidence of recurrent preeclampsia from women with previous preeclampsia regarding the time of onset (A) or the severity of preeclampsia (B) in first pregnancy.
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preeclampsia either with the time of onset (p = 0.290) or the severity of preeclampsia in the first pregnancy (p = 0.973) (Fig. 1). We then compared the time of onset or the severity of preeclampsia in first pregnancy with the time of onset or the severity of preeclampsia in second pregnancy in recurrent preeclampsia. Thirty out of 32 (93.7%) women with previous early onset preeclampsia developed early onset preeclampsia in second pregnancy and 13 out of 23 (56.5%) women with previous late onset preeclampsia developed early onset preeclampsia in second pregnancy. There was a significant association in the development of early onset preeclampsia between the first pregnancy and the second pregnancy (p = 0.001) (Fig. 2A). Twenty five out of 34 (73.5%) women with previous severe preeclampsia developed severe recurrent preeclampsia and 16 out of 21 (76.2%) women with previous mild preeclampsia developed severe preeclampsia in second pregnancy. There was no significant association in the severity of preeclampsia between the first pregnancy and the second pregnancy (p = 0.998) (Fig. 2B). The baby weight in recurrent preeclampsia was significantly decreased compared to that in first pregnancy with preeclampsia (p = 0.03).
[(Fig._2)TD$IG]
A
Women developed preeclampsia (N=1252)
Subsequent pregnancy (N=92)
Recurrent preeclampsia (N=55)
1st pregnancy early onset (N=32)
1st pregnancy late onset (N=23)
2nd pregnancy early onset (N=30, 93.7%)
2nd pregnancy early onset (N=13, 56.5%)
B Women developed preeclampsia (N=1252)
Subsequent pregnancy (N=92)
Recurrent preeclampsia (N=55)
1st pregnancy severe preeclampsia (N=34)
1st Pregnancy mild preeclampsia (N=21)
2nd pregnancy severe 25 preeclampsia (N=25, 73.5%)
2nd pregnancy severe preeclampsia (N=16, 76.2%)
Fig. 2. Flow diagram showing the obstetrical outcome of subsequent pregnancies regarding the time of onset (A) or the severity of preeclampsia (B) in first pregnancy.
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Comments Women with a history of preeclampsia have an increased risk of developing recurrent preeclampsia in future pregnancies. Whether the severity or the time of onset of preeclampsia in first pregnancy is associated with the incidence of recurrent preeclampsia, and with the severity and the time of onset in recurrent preeclampsia are unclear. In this study we found that the incidence of recurrent preeclampsia is not associated with the severity and the time of onset of preeclampsia in first pregnancy. However women with previous early onset preeclampsia are more likely to develop early onset preeclampsia in second pregnancy. In addition, we also found that women are more likely to develop severe preeclampsia in second pregnancy regardless the severity of preeclampsia in first pregnancy. A number of studies have shown that the incidence of recurrent preeclampsia is 13 to 65% [5–7]. In this study our data showed that the incidence of recurrent preeclampsia was 59.8% which was similar to other studies. Although our recent study showed that the incidence of primary preeclampsia is 1.92% in Chinese population which is lower than most western countries [11], the incidence of recurrent preeclampsia in Chinese population reported in this study is higher. We currently do not know the reason for this higher incidence of recurrent preeclampsia but it may be women with previous preeclampsia are more likely to develop recurrent preeclampsia in Chinese population due to environmental or genetic factor(s). The incidence of recurrent preeclampsia is higher in women with chronic hypertension or a higher BMI. In this study, no women had history of chronic hypertension before the second pregnancy. Although increased BMI was associated with the incidence of preeclampsia, there was no significant difference in BMI between the two pregnancies in women developed recurrent preeclampsia. The incidence of recurrent preeclampsia is dependent on the preeclampsia status in previous pregnancies. It has been suggested that in women with a history of preeclampsia, particularly if the time of delivery is before 28 weeks in first pregnancy that there is a 4 fold increased for developing recurrent preeclampsia compared to those where the time of delivery is after 37 weeks in first pregnancy [12]. However, in that report [12] it was not stated whether the incidence of recurrent preeclampsia in subsequent pregnancies was associated with the time of onset or the severity in first pregnancy. Other studies have only investigated the association of delivery time in women with preeclampsia in first pregnancy with the incidence of recurrent preeclampsia [4,12,13]. These studies have suggested that early delivery in first pregnancy increases the likelihood of recurrent preeclampsia. In addition, some studies have not specified the differences in the time of onset or the severity in first pregnancy [5]. Whether the time of onset or the severity in the first pregnancy is associated with the incidence of recurrent preeclampsia are fully understood. In this study our data showed that the gestation at presentation in the first pregnancy in women who developed recurrent preeclampsia was significantly earlier than in women who did not develop recurrent preeclampsia (32 versus 35 weeks), but the incidence of recurrent preeclampsia was not significantly different. Furthermore in this study our data showed that 65.3% of all women with early onset preeclampsia in first pregnancy developed recurrent preeclampsia and 53.4% of all women with late onset preeclampsia in first pregnancy developed recurrent preeclampsia. There was no significant increase in the incidence of recurrent preeclampsia regarding the time of onset. In addition, our data also showed that 59.6% of all women with severe preeclampsia in first pregnancy developed recurrent preeclampsia and 60% women with mild preeclampsia in first pregnancy developed recurrent preeclampsia. There was also no significant
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increase in the incidence of recurrent preeclampsia regarding on the severity of preeclampsia. Our result was consistent with the study by van Rijn and colleagues which suggested that the incidence of recurrent preeclampsia was not associated with the severity of preeclampsia in first pregnancy [14]. Taken together, our data showed that neither the time of onset nor the severity of preeclampsia in first pregnancy was associated with the incidence of recurrent preeclampsia. Among all cases of the preeclampsia, approximately 10% develop early onset and 25% develop severe preeclampsia [15,16]. Studies indicated that the recurrent preeclampsia rate in severe disease is about 20–25% in subsequent pregnancies. Whether the time of onset or the severity of preeclampsia in first pregnancy is associated with the time of onset or the severity of preeclampsia in second pregnancy has not been studied. In this study our data showed that 93.7% women who developed early onset recurrent preeclampsia experienced early onset preeclampsia in first pregnancy. In contrast, only 56.5% women who experienced late onset preeclampsia in first pregnancy developed early onset recurrent preeclampsia. There was a significant association with the time of onset between first pregnancy and second pregnancy, suggesting the risk of recurrence in developing early onset preeclampsia in second pregnancy is higher when women developed early onset preeclampsia in first pregnancy. A previous study reported that the incidence of early onset recurrent preeclampsia is significantly lower in women with previous early onset preeclampsia compared with women with previous early onset preeclampsia who developed late recurrent preeclampsia [14]. This difference could be because in our study, the population includes women with early onset and late onset preeclampsia in first pregnancy whereas in van Rijn’s study [14], the study population only included women with early onset preeclampsia in first pregnancy. In addition, in our study all the women with previous preeclampsia only received calcium supplementation when they were in second pregnancy, however in van Rijn’s study [14], all the women with early onset preeclampsia in first pregnancy received the treatment with low dose aspirin from 12 weeks to 36 weeks in second pregnancy which may have led to a lower incidence of recurrent preeclampsia (25%) or lower incidence of early onset recurrent preeclampsia compared to our current study. Our results here may suggest the time of onset in first pregnancy may link to the time of onset in second pregnancy. Although in this current study our data showed that 73.5% women who experienced severe preeclampsia in first pregnancy developed severe preeclampsia in second pregnancy, which was not significantly different to women who developed mild preeclampsia in first pregnancy developed severe preeclampsia in second pregnancy (76.2%), this result suggests that the severity of recurrent preeclampsia is increased in even women with mild preeclampsia in their first pregnancy. Our data also showed the gestation at presentation in the first pregnancy in women who developed recurrent preeclampsia was significantly earlier than in women who did not develop recurrent preeclampsia, suggesting women who experienced early onset preeclampsia in their first pregnancy are likely to develop recurrent preeclampsia. Taken together these results suggest that even women with mild preeclampsia in first pregnancy should be monitored very early in their future pregnancy. Studies suggested that a prolonged interval between pregnancies is positively associated with the incidence of preeclampsia in women without previous preeclampsia and without changing the paternity [4,17]. When the interval between pregnancies was 10 years or more, the risk of developing preeclampsia was about the same as that in nulliparous women [3]. The incidence of recurrent preeclampsia was increased by 1.12 fold for each year increase in
the interval [3]. In this study, our data showed that median interval between the first and second pregnancy in women who developed recurrent preeclampsia was 4 years which was significantly longer than that in women who did not develop recurrent preeclampsia. Taken together our data suggest that a prolonged interval between pregnancies is also associated with recurrent preeclampsia. Studies have shown that low baby weight in a first pregnancy with preeclampsia is significantly associated with the incidence of recurrent preeclampsia [18,19]. However a recent study showed that there was no significant difference in the incidence of recurrent preeclampsia in the baby weight between women who developed and who did not develop recurrent preeclampsia [20]. In this current study our data also showed that the baby weight in first pregnancy was not associated with the incidence of recurrent preeclampsia. However, in this current study we found that the baby weight was significant lower in recurrent preeclampsia compared with that in first preeclampsia, suggesting that severity in overall of recurrent preeclampsia is increased. Changing sexual partners increases the risk of developing preeclampsia, possible due to immunologic reaction. In our study population, only one woman who developed recurrent preeclampsia changed her sexual partner in second pregnancy. Therefore we were not able to address this issue. There was a limitation of this study on the population size. Therefore the conclusion made by this study needs future large studies to be confirmed. It is impossible to predict the perinatal outcome in subsequent pregnancies in individual woman with previous preeclampsia, even though few studies investigated the potential biomarkers to predict recurrent preeclampsia [21]. In conclusion, in this study our data show that neither the time of onset, nor the severity of preeclampsia was associated with the incidence of recurrent preeclampsia, but the gestation week at onset in the first pregnancy was positively associated with the gestation week at onset in second pregnancy, suggesting women with early onset preeclampsia in first pregnancy are more likely to experience early onset preeclampsia in second pregnancy. Close obstetrical monitoring for women with previous preeclampsia is necessary during a subsequent pregnancy. Condensation Women with early onset preeclampsia in first pregnancy are more likely to experience early onset preeclampsia in subsequent pregnancies. Conflict of interest None of the authors have a conflict interest. Acknowledgement This study was supported by the grant from National Key Discipline of Obstetrics of China. References [1] Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365(9461):785– 99. [2] Berg CJ, Atrash HK, Koonin LM, Tucker M. Pregnancy-related mortality in the United States, 1987–1990. Obstet Gynecol 1996;88(2):161–7. [3] Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 2005;330(7491):565. [4] Hernandez-Diaz S, Toh S, Cnattingius S. Risk of pre-eclampsia in first and subsequent pregnancies: prospective cohort study. BMJ 2009;338:b2255. [5] Lie RT, Rasmussen S, Brunborg H, Gjessing HK, Lie-Nielsen E, Irgens LM. Fetal and maternal contributions to risk of pre-eclampsia: population based study. BMJ 1998;316(7141):1343–7.
X.L. Li et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 177 (2014) 94–99 [6] 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(5):1011–6. [7] Sibai BM, Mercer B, Sarinoglu C. Severe preeclampsia in the second trimester: recurrence risk and long-term prognosis. Am J Obstet Gynecol 1991;165(5 Pt 1):1408–12. [8] Barton JR, Sibai BM. Prediction and prevention of recurrent preeclampsia. Obstet Gynecol 2008;112(2 Pt 1):359–72. [9] Makkonen N, Heinonen S, Kirkinen P. Obstetric prognosis in second pregnancy after preeclampsia in first pregnancy. Hypertens Pregnancy 2000;19(2):173–81. [10] Roberts JM, Pearson GD, Cutler JA, Lindheimer MD. Summary of the NHLBI working group on research on hypertension during pregnancy. Hypertens Pregnancy 2003;22(2):109–27. [11] Xiao JP, Shen F, Xue Q, et al. Is ethnicity a risk factor for developing preeclampsia? An analysis of the prevalence of preeclampsia in China. J Hum Hypertens 2014. http://dx.doi.org/10.1038/jhh.2013.148 (in press). [12] Lykke JA, Paidas MJ, Langhoff-Roos J. Recurring complications in second pregnancy. Obstet Gynecol 2009;113(6):1217–24. [13] Langenveld J, Buttinger A, van der Post J, Wolf H, Mol BW, Ganzevoort W. Recurrence risk and prediction of a delivery under 34 weeks of gestation after a history of a severe hypertensive disorder. BJOG 2011;118(5):589–95.
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[14] van Rijn BB, Hoeks LB, Bots ML, Franx A, Bruinse HW. Outcomes of subsequent pregnancy after first pregnancy with early-onset preeclampsia. Am J Obstet Gynecol 2006;195(3):723–8. [15] Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: lessons learned from recent trials. Am J Obstet Gynecol 2004;190(6):1520–6. [16] Sibai BM. Magnesium sulfate prophylaxis in preeclampsia: evidence from randomized trials. Clin Obstet Gynecol 2005;48(2):478–88. [17] Basso O, Olsen J. Sex ratio and twinning in women with hyperemesis or preeclampsia. Epidemiology 2001;12(6):747–9. [18] Rasmussen S, Irgens LM, Albrechtsen S, Dalaker K. Predicting preeclampsia in the second pregnancy from low birth weight in the first pregnancy. Obstet Gynecol 2000;96(5 Pt 1):696–700. [19] Campbell DM, MacGillivray I, Carr-Hill R. Pre-eclampsia in second pregnancy. Br J Obstet Gynaecol 1985;92(2):131–40. [20] Gaugler-Senden IP, Berends AL, de Groot CJ, Steegers EA. Severe, very early onset preeclampsia: subsequent pregnancies and future parental cardiovascular health. Eur J Obstet Gynecol Reprod Biol 2008;140(2): 171–7. [21] Sep SJ, Smits LJ, Prins MH, Spaanderman ME, Peeters LL. Simple prepregnant prediction rule for recurrent early-onset hypertensive disease in pregnancy. Reprod Sci 2009;16(1):80–7.
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European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
Early onset preeclampsia in subsequent pregnancies correlates with early onset preeclampsia in first pregnancy X.L. Li a, T.T. Chen a, X. Dong a, W.L. Gou a, S. Lau b, P. Stone b, Q. Chen b,c,* a
Department of Obstetrics & Gynaecology, First affiliated Hospital of Xi’an Jiaotong University, Xi’an, China Department of Obstetrics & Gynaecology, The University of Auckland, Auckland, New Zealand c The Hospital of Obstetrics & Gynaecology, Fudan University, Shanghai, China b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 12 December 2013 Received in revised form 13 March 2014 Accepted 31 March 2014
Objective: Preeclampsia is a major complication of pregnancy and its occurrence in a first pregnancy is a major risk factor for recurrence in subsequent pregnancies. Whether the time of onset or the severity of preeclampsia in a first pregnancy is associated with the incidence of recurrent preeclampsia is not clear. We performed a retrospective study to analyse the incidence of recurrent preeclampsia and associations of the time of onset and the severity of preeclampsia between first preeclampsia and recurrent preeclampsia. Study design: Ninety-two women with previous preeclampsia who had a second pregnancy in a 4 year period were included. Data on the first and second pregnancies were obtained and included maternal age, maternal height and weight, gestation week at onset of preeclampsia and at delivery, blood pressure, proteinuria, interval between pregnancies and birth weights. Results: Fifty-five women with previous preeclampsia developed recurrent preeclampsia (59.8%). The difference in the incidence of recurrent early and late onset preeclampsia was not significant different (65.3% versus 53.4%, p > 0.05). The difference in the incidence of mild or severe disease in those who experienced recurrent preeclampsia was also not significant (59.6% versus 60%, p > 0.05). The severity of preeclampsia in second pregnancy was not associated with the severity of preeclampsia in first pregnancy. However 93.7% women with previous early onset preeclampsia developed early onset preeclampsia in second pregnancy and 56.5% women with previous late onset preeclampsia developed early onset preeclampsia in second pregnancy. In addition, 76.2% women with previous mild preeclampsia developed severe preeclampsia in second pregnancy. The baby weight in recurrent preeclampsia was significantly decreased compared to that in first pregnancy with preeclampsia. Conclusion: Our data demonstrate that there was no association between the incidence of recurrent preeclampsia and the time of onset or severity of preeclampsia in first pregnancy. But our data here may suggest that women with early onset preeclampsia in first pregnancy are more likely to experience early onset preeclampsia in second pregnancy. The severity of recurrent preeclampsia is increased regardless the severity in first pregnancy. ß 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Recurrent preeclampsia Time of onset Severity Preeclampsia China
Introduction Preeclampsia is a placental specific disorder that becomes clinically apparent after 20 weeks of gestation or within the first 4– 6 weeks postpartum. Preeclampsia can affect both the mother and the unborn baby and is estimated to affect between 5 and 8% of
* Corresponding author at: 419 Fang Xie Road, The Hospital of Obstetrics & Gynaecology, Fudan University, Shanghai, China. Tel.: +86 13611691734/+64 992 35645; fax: +86 21 63455090. E-mail address: [email protected] (Q. Chen). http://dx.doi.org/10.1016/j.ejogrb.2014.03.043 0301-2115/ß 2014 Elsevier Ireland Ltd. All rights reserved.
healthy pregnancies [1]. It is responsible for about 76,000 maternal deaths and 500,000 infant deaths per year [2]. The clinical symptoms and signs of preeclampsia are high blood pressure, proteinuria, sudden weight gain, headaches, swelling and blurred vision and risk of eclampsia in addition to fetal complications including growth restriction and stillbirth. Although the pathogenesis of preeclampsia is not fully understood, it is widely accepted that both maternal and placental factors contribute to the pathogenesis of this disease. It is primarily a disease of endothelial activation, inflammation, vasoconstriction and multi-organ damage. Maternal risk factors at antenatal include maternal age, parity, previous preeclampsia, multiple pregnancy, body mass index (BMI) and pre-existing
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medical conditions such as antiphospholipid antibodies syndromes [3], and chronic hypertension or renal disease. Of these risk factors, women with previous preeclampsia, particularly if the onset had been before the third trimester have seven times the risk of developing preeclampsia in a second pregnancy suggesting previous preeclampsia is the single largest risk factor for developing recurrent preeclampsia [4]. Although there are not many studies looking at the incidence of recurrent preeclampsia in subsequent pregnancies, studies showed that the incidence of recurrent preeclampsia is around 13 to 65% depending on the time of onset and the severity of preeclampsia in the first pregnancy [5–7]. It has also been suggested that there are geographical variations in incidence of preeclampsia [5–7]. To reduce the risk of recurrent preeclampsia, there is growing evidence suggesting that low dose aspirin, calcium or possibly folic acid supplementation may have some benefits for women who suffered preeclampsia in a previous pregnancy. Most previous studies have focused on the incidence of recurrent preeclampsia and potential risk factors for this in subsequent pregnancies in women with a prior history of the condition [3,4,8,9]. Whether the time of onset or the severity of preeclampsia in first pregnancy is associated with the incidence of recurrent preeclampsia is far from clear. In addition, only a few studies have compared women with previous preeclampsia who developed recurrent preeclampsia with who did not develop recurrent preeclampsia. China instituted a ‘‘one child policy’’ at the end of the 1970s, however after 30 years of strict enforcement, recently it has become apparent that there has been relaxation in the application of that policy. Therefore we undertook this study to analyse the incidence of recurrent preeclampsia in subsequent pregnancies in women with a history of preeclampsia and to define the potential maternal risk factors for recurrent preeclampsia. Material and methods Study population This retrospective study was performed at a university teaching hospital serving a diverse urban and rural population of around 8 million in China. Data on 92 primiparous women with previous preeclampsia was collected from Department of Obstetrics and Gynaecology, First Hospital of Xian, Jiaotong University of China from January 2008 to December 2012. Data recorded included maternal age, maternal height and weight, gestation at presentation of preeclampsia, gestation at delivery, blood pressure on admission, proteinuria, baby weight, interval between two pregnancies (live birth), partner information (whether changed the partners in second pregnancy), and delivery modes in the first and second pregnancies. All women were non-smoking and had no family history of preeclampsia. In the second pregnancy, all patients received treatment with calcium supplementation after 12 weeks gestation. Of the 92 primiparous women, 55 women developed recurrent preeclampsia. Preeclampsia was defined as a maternal systolic blood pressure 140 mmHg and/or diastolic blood pressure 90 mmHg measured on two occasions separated by at least 6 h, and proteinuria >300 mg on a 24 h urinary collection or qualitatively, >1+, after 20 weeks of gestation following the guidelines of the International Society for the Study of Hypertension in Pregnancy (ISSHP) [10]. Maternal systolic blood pressure 160 mmHg and/or diastolic blood pressure 110 mmHg on admission was defined as severe preeclampsia. Early onset preeclampsia was defined as occurring at less than 34 weeks. Body mass index (BMI) was calculated as the ratio of maternal weight and height (kg/m2) at the first booking visit (around 12 weeks of gestation). According to the WHO classification of BMI for Asian/Indian women, the BMI for normal,
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overweight and obese is 18.5–22.9 kg/m2, 23–27.4 kg/m2 and greater than 27.5 kg/m2, respectively. Statistical analysis The statistical differences in maternal age, gestation week at presentation or delivery in the first pregnancy or second pregnancy, and birth weight, and BMI between women with recurrent preeclampsia and without recurrent preeclampsia were assessed by Mann–Whitney U-test using Prism software package. The statistical differences in the incidence of recurrent preeclampsia in relationship to the severity or the time of onset of preeclampsia between recurrent preeclampsia and no recurrent preeclampsia were assessed by a Fisher’s exact test using Prism software. p-Values of <0.05 were considered significant. Results There were 1252 women who developed preeclampsia from January 2008 to December 2012 in the Department of Obstetrics & Gynaecology, First Hospital of Xian, Jiaotong University. Of these, 92 primiparous women with previous preeclampsia had subsequent pregnancies and of these, 55 women developed recurrent preeclampsia. The incidence of recurrent preeclampsia was 59.8%. The general clinical characteristics of the women with previous preeclampsia (n = 92) are summarised in Table 1. In the first Table 1 The clinical characteristics of the women with preeclampsia and recurrent preeclampsia. Women with or without recurrent preeclampsia Recurrent PE (N = 55) Characteristics of the first pregnancy (N = 92) Maternal age (years, median/range) 25 (21–37) Gestation week at presentation 32 (18–41)* Gestation week at delivery 36 (23–41) (median/range) Baby weight (g, median/range) 3073 (1345–3865) Systolic BP (mmHg, median/range) 160 (140–185) Diastolic BP (mmHg, median/range) 100 (90–110) Proteinuria +–+++ Stillbirth 2 (3.6%) Body mass index (BMI) 24.13 (20.32–30.39)* Delivery model Vaginal delivery (number of women) 13 Caesarean section (number of women) 42 Characteristics of the second pregnancy (N = 92) Maternal age (years, median/range) 32 (20–40) Gestation week at presentation 34 (18–41) Gestation week at delivery 35 (24–41)* (median/range) Baby weight (g, median/range) 2778 (1513–3446)#,* Systolic BP (mmHg, median/range) 165 (130–220)* Diastolic BP (mmHg, median/range) 110 (90–140)* Proteinuria +–+++ Stillbirth 2 (3.6%) Body mass index (BMI) 23.53 (19.95–29.14)* Time interval between pregnancies 4 (1–16)* (years) Delivery model Vaginal delivery (number of women) 18 Caesarean section (number of women) 37
No recurrent PE (N = 37) 25 (19–33) 35 (26–42) 36 (32–42) 3201 (2015–3810) 160 (140–200) 100 (90–130) +–+++ 1 (2.7%) 22.04 (19.92–24.13) 5 32 27 (22–36) N/A 39 (36–41) 3276 (2715–3655) 125 (110–135) 75 (65–85) Negative 0 21.63 (19.72–25.15) 3 (1–6)
3 34
* p < 0.05, Women who developed recurrent preeclampsia versus women who did not develop recurrent preeclampsia. # p = 0.03, baby weight in first pregnancy versus in second pregnancy in women who developed recurrent preeclampsia.
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pregnancy, the median maternal age in 55 primiparous women who developed recurrent preeclampsia was 25 years old (range 21 to 37 years). The median gestation at presentation was 32 weeks (range18 to 41 weeks). The median baby weight was 3073 g (range 1345 to 3865 g). In the 37 primiparous women who did not develop recurrent preeclampsia, the median maternal age was 25 years old (range 19 to 33 years). The median gestation at presentation was 35 weeks (range 26 to 42 weeks). The median baby weight was 3201 g (range 2015 to 3810 g). There was no significant difference in maternal age, gestation at delivery, baby weight and blood pressure on admission in first pregnancy between women who did or did not develop recurrent preeclampsia. However preeclampsia presented significantly earlier in the first pregnancy in those who developed recurrent disease than those who did not have preeclampsia in the subsequent pregnancy (32 versus 35 weeks, p = 0.017). In addition, the BMI in first pregnancy in women who developed recurrent preeclampsia was significant higher than that in women who did not develop recurrent preeclampsia (24.13 versus 22.04, p = 0.001). In the second pregnancy, the gestation weeks at delivery and birth weight were significantly lower in women who developed recurrent preeclampsia than in women who did not (p = 0.001). The BMI in women who developed recurrent preeclampsia was
significantly higher than in those women who did not develop recurrent preeclampsia (p = 0.001). The median interval between pregnancies (live birth) in women who developed recurrent preeclampsia was significantly longer than that in women who did not develop recurrent preeclampsia (4 years versus 3 years, p = 0.005) (Table 1). When we divided 92 women with previous preeclampsia by the time of onset in first pregnancy, 49 women developed early onset preeclampsia and 43 women developed late onset preeclampsia. When we divided 92 women with previous preeclampsia by the severity of preeclampsia in first pregnancy, 57 women developed severe preeclampsia and 35 women developed mild preeclampsia divided in first pregnancy. We analysed whether the time of onset or the severity of preeclampsia in first pregnancy was associated with the incidence of recurrent preeclampsia. Thirty two out of 49 (65.3%) women with previous early onset preeclampsia developed recurrent preeclampsia and 23 out of 43 (53.4%) women with previous late onset preeclampsia developed recurrent preeclampsia. Thirty four out of 57 (59.6%) women with previous severe preeclampsia developed recurrent preeclampsia and 21 out of 35 (60%) women with previous mild preeclampsia developed recurrent preeclampsia. There was no significant association of incidence of recurrent
[(Fig._1)TD$IG] A Early onset preeclampsia in first pregnancy (N=49)
Recurrent Preeclampsia (N=32, 65.3%)
Early Onset Recurrent Preeclampsia (N=30, 93.7%)
NO Recurrent Preeclampsia (N=17, 34.7%)
Late onset Recurrent Preeclampsia (N=2, 6.3%)
Late onset preeclampsia in first pregnancy (N=43)
Recurrent Preeclampsia (N=23, 53.4%)
Early Onset Recurrent Preeclampsia (N=13, 56.5%)
NO Recurrent Preeclampsia (N=20, 46.6%)
Late onset Recurrent Preeclampsia (N=10, 43.5%)
B Severe preeclampsia in first pregnancy (N=57)
Recurrent Preeclampsia (N=34, 59.6%)
Severe Recurrent Preeclampsia (N=25, 73.5%)
NO Recurrent Preeclampsia (N=23, 40.4%)
Mild Recurrent Preeclampsia (N=9, 26.5%)
Mild preeclampsia in first pregnancy (N=35)
Recurrent Preeclampsia (N=21, 60.0%)
Severe Recurrent Preeclampsia (N=16, 76.2%)
NO Recurrent Preeclampsia (N=14, 40%)
Mild Recurrent Preeclampsia (N=5, 23.8%)
Fig. 1. Flow diagram showing the incidence of recurrent preeclampsia from women with previous preeclampsia regarding the time of onset (A) or the severity of preeclampsia (B) in first pregnancy.
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preeclampsia either with the time of onset (p = 0.290) or the severity of preeclampsia in the first pregnancy (p = 0.973) (Fig. 1). We then compared the time of onset or the severity of preeclampsia in first pregnancy with the time of onset or the severity of preeclampsia in second pregnancy in recurrent preeclampsia. Thirty out of 32 (93.7%) women with previous early onset preeclampsia developed early onset preeclampsia in second pregnancy and 13 out of 23 (56.5%) women with previous late onset preeclampsia developed early onset preeclampsia in second pregnancy. There was a significant association in the development of early onset preeclampsia between the first pregnancy and the second pregnancy (p = 0.001) (Fig. 2A). Twenty five out of 34 (73.5%) women with previous severe preeclampsia developed severe recurrent preeclampsia and 16 out of 21 (76.2%) women with previous mild preeclampsia developed severe preeclampsia in second pregnancy. There was no significant association in the severity of preeclampsia between the first pregnancy and the second pregnancy (p = 0.998) (Fig. 2B). The baby weight in recurrent preeclampsia was significantly decreased compared to that in first pregnancy with preeclampsia (p = 0.03).
[(Fig._2)TD$IG]
A
Women developed preeclampsia (N=1252)
Subsequent pregnancy (N=92)
Recurrent preeclampsia (N=55)
1st pregnancy early onset (N=32)
1st pregnancy late onset (N=23)
2nd pregnancy early onset (N=30, 93.7%)
2nd pregnancy early onset (N=13, 56.5%)
B Women developed preeclampsia (N=1252)
Subsequent pregnancy (N=92)
Recurrent preeclampsia (N=55)
1st pregnancy severe preeclampsia (N=34)
1st Pregnancy mild preeclampsia (N=21)
2nd pregnancy severe 25 preeclampsia (N=25, 73.5%)
2nd pregnancy severe preeclampsia (N=16, 76.2%)
Fig. 2. Flow diagram showing the obstetrical outcome of subsequent pregnancies regarding the time of onset (A) or the severity of preeclampsia (B) in first pregnancy.
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Comments Women with a history of preeclampsia have an increased risk of developing recurrent preeclampsia in future pregnancies. Whether the severity or the time of onset of preeclampsia in first pregnancy is associated with the incidence of recurrent preeclampsia, and with the severity and the time of onset in recurrent preeclampsia are unclear. In this study we found that the incidence of recurrent preeclampsia is not associated with the severity and the time of onset of preeclampsia in first pregnancy. However women with previous early onset preeclampsia are more likely to develop early onset preeclampsia in second pregnancy. In addition, we also found that women are more likely to develop severe preeclampsia in second pregnancy regardless the severity of preeclampsia in first pregnancy. A number of studies have shown that the incidence of recurrent preeclampsia is 13 to 65% [5–7]. In this study our data showed that the incidence of recurrent preeclampsia was 59.8% which was similar to other studies. Although our recent study showed that the incidence of primary preeclampsia is 1.92% in Chinese population which is lower than most western countries [11], the incidence of recurrent preeclampsia in Chinese population reported in this study is higher. We currently do not know the reason for this higher incidence of recurrent preeclampsia but it may be women with previous preeclampsia are more likely to develop recurrent preeclampsia in Chinese population due to environmental or genetic factor(s). The incidence of recurrent preeclampsia is higher in women with chronic hypertension or a higher BMI. In this study, no women had history of chronic hypertension before the second pregnancy. Although increased BMI was associated with the incidence of preeclampsia, there was no significant difference in BMI between the two pregnancies in women developed recurrent preeclampsia. The incidence of recurrent preeclampsia is dependent on the preeclampsia status in previous pregnancies. It has been suggested that in women with a history of preeclampsia, particularly if the time of delivery is before 28 weeks in first pregnancy that there is a 4 fold increased for developing recurrent preeclampsia compared to those where the time of delivery is after 37 weeks in first pregnancy [12]. However, in that report [12] it was not stated whether the incidence of recurrent preeclampsia in subsequent pregnancies was associated with the time of onset or the severity in first pregnancy. Other studies have only investigated the association of delivery time in women with preeclampsia in first pregnancy with the incidence of recurrent preeclampsia [4,12,13]. These studies have suggested that early delivery in first pregnancy increases the likelihood of recurrent preeclampsia. In addition, some studies have not specified the differences in the time of onset or the severity in first pregnancy [5]. Whether the time of onset or the severity in the first pregnancy is associated with the incidence of recurrent preeclampsia are fully understood. In this study our data showed that the gestation at presentation in the first pregnancy in women who developed recurrent preeclampsia was significantly earlier than in women who did not develop recurrent preeclampsia (32 versus 35 weeks), but the incidence of recurrent preeclampsia was not significantly different. Furthermore in this study our data showed that 65.3% of all women with early onset preeclampsia in first pregnancy developed recurrent preeclampsia and 53.4% of all women with late onset preeclampsia in first pregnancy developed recurrent preeclampsia. There was no significant increase in the incidence of recurrent preeclampsia regarding the time of onset. In addition, our data also showed that 59.6% of all women with severe preeclampsia in first pregnancy developed recurrent preeclampsia and 60% women with mild preeclampsia in first pregnancy developed recurrent preeclampsia. There was also no significant
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increase in the incidence of recurrent preeclampsia regarding on the severity of preeclampsia. Our result was consistent with the study by van Rijn and colleagues which suggested that the incidence of recurrent preeclampsia was not associated with the severity of preeclampsia in first pregnancy [14]. Taken together, our data showed that neither the time of onset nor the severity of preeclampsia in first pregnancy was associated with the incidence of recurrent preeclampsia. Among all cases of the preeclampsia, approximately 10% develop early onset and 25% develop severe preeclampsia [15,16]. Studies indicated that the recurrent preeclampsia rate in severe disease is about 20–25% in subsequent pregnancies. Whether the time of onset or the severity of preeclampsia in first pregnancy is associated with the time of onset or the severity of preeclampsia in second pregnancy has not been studied. In this study our data showed that 93.7% women who developed early onset recurrent preeclampsia experienced early onset preeclampsia in first pregnancy. In contrast, only 56.5% women who experienced late onset preeclampsia in first pregnancy developed early onset recurrent preeclampsia. There was a significant association with the time of onset between first pregnancy and second pregnancy, suggesting the risk of recurrence in developing early onset preeclampsia in second pregnancy is higher when women developed early onset preeclampsia in first pregnancy. A previous study reported that the incidence of early onset recurrent preeclampsia is significantly lower in women with previous early onset preeclampsia compared with women with previous early onset preeclampsia who developed late recurrent preeclampsia [14]. This difference could be because in our study, the population includes women with early onset and late onset preeclampsia in first pregnancy whereas in van Rijn’s study [14], the study population only included women with early onset preeclampsia in first pregnancy. In addition, in our study all the women with previous preeclampsia only received calcium supplementation when they were in second pregnancy, however in van Rijn’s study [14], all the women with early onset preeclampsia in first pregnancy received the treatment with low dose aspirin from 12 weeks to 36 weeks in second pregnancy which may have led to a lower incidence of recurrent preeclampsia (25%) or lower incidence of early onset recurrent preeclampsia compared to our current study. Our results here may suggest the time of onset in first pregnancy may link to the time of onset in second pregnancy. Although in this current study our data showed that 73.5% women who experienced severe preeclampsia in first pregnancy developed severe preeclampsia in second pregnancy, which was not significantly different to women who developed mild preeclampsia in first pregnancy developed severe preeclampsia in second pregnancy (76.2%), this result suggests that the severity of recurrent preeclampsia is increased in even women with mild preeclampsia in their first pregnancy. Our data also showed the gestation at presentation in the first pregnancy in women who developed recurrent preeclampsia was significantly earlier than in women who did not develop recurrent preeclampsia, suggesting women who experienced early onset preeclampsia in their first pregnancy are likely to develop recurrent preeclampsia. Taken together these results suggest that even women with mild preeclampsia in first pregnancy should be monitored very early in their future pregnancy. Studies suggested that a prolonged interval between pregnancies is positively associated with the incidence of preeclampsia in women without previous preeclampsia and without changing the paternity [4,17]. When the interval between pregnancies was 10 years or more, the risk of developing preeclampsia was about the same as that in nulliparous women [3]. The incidence of recurrent preeclampsia was increased by 1.12 fold for each year increase in
the interval [3]. In this study, our data showed that median interval between the first and second pregnancy in women who developed recurrent preeclampsia was 4 years which was significantly longer than that in women who did not develop recurrent preeclampsia. Taken together our data suggest that a prolonged interval between pregnancies is also associated with recurrent preeclampsia. Studies have shown that low baby weight in a first pregnancy with preeclampsia is significantly associated with the incidence of recurrent preeclampsia [18,19]. However a recent study showed that there was no significant difference in the incidence of recurrent preeclampsia in the baby weight between women who developed and who did not develop recurrent preeclampsia [20]. In this current study our data also showed that the baby weight in first pregnancy was not associated with the incidence of recurrent preeclampsia. However, in this current study we found that the baby weight was significant lower in recurrent preeclampsia compared with that in first preeclampsia, suggesting that severity in overall of recurrent preeclampsia is increased. Changing sexual partners increases the risk of developing preeclampsia, possible due to immunologic reaction. In our study population, only one woman who developed recurrent preeclampsia changed her sexual partner in second pregnancy. Therefore we were not able to address this issue. There was a limitation of this study on the population size. Therefore the conclusion made by this study needs future large studies to be confirmed. It is impossible to predict the perinatal outcome in subsequent pregnancies in individual woman with previous preeclampsia, even though few studies investigated the potential biomarkers to predict recurrent preeclampsia [21]. In conclusion, in this study our data show that neither the time of onset, nor the severity of preeclampsia was associated with the incidence of recurrent preeclampsia, but the gestation week at onset in the first pregnancy was positively associated with the gestation week at onset in second pregnancy, suggesting women with early onset preeclampsia in first pregnancy are more likely to experience early onset preeclampsia in second pregnancy. Close obstetrical monitoring for women with previous preeclampsia is necessary during a subsequent pregnancy. Condensation Women with early onset preeclampsia in first pregnancy are more likely to experience early onset preeclampsia in subsequent pregnancies. Conflict of interest None of the authors have a conflict interest. Acknowledgement This study was supported by the grant from National Key Discipline of Obstetrics of China. References [1] Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet 2005;365(9461):785– 99. [2] Berg CJ, Atrash HK, Koonin LM, Tucker M. Pregnancy-related mortality in the United States, 1987–1990. Obstet Gynecol 1996;88(2):161–7. [3] Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 2005;330(7491):565. [4] Hernandez-Diaz S, Toh S, Cnattingius S. Risk of pre-eclampsia in first and subsequent pregnancies: prospective cohort study. BMJ 2009;338:b2255. [5] Lie RT, Rasmussen S, Brunborg H, Gjessing HK, Lie-Nielsen E, Irgens LM. Fetal and maternal contributions to risk of pre-eclampsia: population based study. BMJ 1998;316(7141):1343–7.
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